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                 UNITED STATES OF AMERICA

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           THE PRESIDENT'S COUNCIL ON BIOETHICS

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                      THIRD MEETING

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                        Thursday,

                      April 25, 2002

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            The Council met at 8:30 a.m., in the Dewey
Rooms of the Hilton Crystal City, 2399 Jefferson Davis
Highway, Arlington, Virginia, Dr. Leon Kass, Chairman,
presiding.

PRESENT:

      LEON R. KASS, M.D., PH.D., Chairman
      ELIZABETH H. BLACKBURN, Ph.D., Member
      REBECCA S. DRESSER, J.D., Member
      DANIEL W. FOSTER, M.D., Member
      FRANCIS FUKUYAMA, Ph.D., Member
      MICHAEL S. GAZZANIGA, Ph.D., Member
      ROBERT P. GEORGE, DPhil, J.D., Member
      MARY ANN GLENDON, J.D., Member
      ALFONSO GOMEZ-LOBO, J.D., Member
      WILLIAM B. HURLBUT, M.D., Member
      CHARLES KRAUTHAMMER, M.D., Member
      PAUL MCHUGH, M.D., Member
      GILBERT C. MEILAENDER, JR., Ph.D., Member
      JANET D. ROWLEY, M.D., D.Sc., Member
      MICHAEL J. SANDEL, D.Phil, Member
      JAMES Q. WILSON, Ph.D., Member
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                   C-O-N-T-E-N-T-S

Session 1: Stem Cells 1: Medical Promise
of Embryonic Stem Cell Research
(Present and Projected)
Dr. John Gearhart ................................. 10

Session 2: Stem Cells 2: Medical Promise
of Adult Stem Cell Research
(Present and Projected)
Dr. Catherine Verfaillie .......................... 88

Session 3: Stem Cells 3: Ethics of Human
Stem Cell Research
Dr. Gene Outka ................................... 171

Session 4: Human Cloning 10: Ethics of
Cloning for Biomedical Research .................. 247

Adjournment ...................................... 315
                                                                            3

1                         P-R-O-C-E-E-D-I-N-G-S

2                                                           (8:43 a.m.)

3                    CHAIRMAN KASS:        Well, I would like to ask

4    Dean Clancy to officially open the meeting, please.

5                    MR. CLANCY:     This meeting is lawful.

6                    DR. KASS:     Thank you very much.          Apologies

7    to our guests and to members of the audience for the

8    late start.       Council Members had to take an oath of

9    office,   which      should   have    been      administered      to    us

10   before our very first meeting.

11                   That has been done and we are now legal in

12   every respect.       Welcome to this, the third meeting of

13   the   President's       Council      on     Bioethics.         We      are

14   expecting colleagues Krauthammer and George today, and

15   Stephen Carter will not be with us, and Bill May will

16   join us tomorrow.

17                   I would like to introduce a new member of

18   our staff, Judy Crawford, who comes to us as the

19   office manager.        Judy, would you please rise so that

20   the   council     members     can    know    you.     We    are     very

21   delighted to have Judy with us.

22                   We   reconvene      as    the    debate    about       the

23   cloning legislation heats up around us, a debate that

24   we did not begin and do not control.                 We are in the

25   midst of our own careful and thorough investigation of
                                                                      4

1    the ethical, social, and policy implications of human

2    cloning seen in its larger scientific, medical, and

3    human contexts.

4                    We have chosen to proceed in a deliberate,

5    collegial, wisdom-seeking, mode in keeping with our

6    charge to inquire fundamentally into the human and

7    moral    significance      of   developments    in      biomedical

8    science and technology.

9                    The most challenging aspect of our inquiry

10   to date has been the moral significance of cloning for

11   biomedical research, a topic discussed for the first

12   time at our last meeting, and to which we return later

13   today in the hope of making progress and clarifying

14   the     contested     moral     issues   at    stake,     and    in

15   articulating the best possible moral arguments for and

16   again the conduct of such research.

17                   On behalf of the council, I would like to

18   thank the staff for its superb work in advancing our

19   inquiry, and on behalf of the staff, I would like to

20   thank council members for their thoughtful comments

21   and responses.       We are in your debt.

22                   The agenda for this meeting brings us into

23   some    new,   but   not   altogether    unrelated,      areas   of

24   inquiry.       Stem cell research, a topic of our first

25   three sessions today.
                                                                                5

1                   Second,      the     question      of     therapy       versus

2    enhancement    as    a    goal    for     the     uses    of    biomedical

3    technology,     and        third,        possible        regulation        of

4    biomedical     technology.             These      topics       have       been

5    selected     with    a     view   to      initiating          one    of    our

6    obligatory future projects, stem cell research, and

7    exploring two possible future projects for the council

8    for the rest of our two year charter.

9                   As     everyone           knows,     in        his      speech

10   announcing    the creation          of    this    council,          President

11   Bush charged us with monitoring stem cell research,

12   embryonic    and     non-embryonic,         human      and     animal,      in

13   order to assess their progress in gaining knowledge

14   and beneficial therapies, and in due course to offer

15   guidelines and regulations for the conduct of such

16   research.

17                  As I indicated at our first meeting, we

18   have begun to collect data that will enable us to

19   describe, assess, and compare the successes achieved

20   with both embryonic and non-embryonic stem cells.

21                  As we are doing this, however, it seemed

22   desirable for council members to learn firsthand, and

23   from some leading researchers in the field, about the

24   scientific     and       therapeutic       promise       of     stem      cell
                                                                                6

1    research    present and          projected; embryonic            and non-

2    embryonic.

3                   And it also seemed desirable to explicitly

4    begin   a   disciplined         conversation       about     the     ethical

5    issues of embryonic stem cell research.                          Our first

6    three sessions today constitute the official thematic

7    beginning of our project on stem cell research.

8                   We        have     of        course         already        been

9    deliberating      about     some       of   these      matters       in    our

10   discussion of human cloning for biomedical research, a

11   topic   that   first      arose     for     us    as   a    crucial       side

12   question of the larger subject of human cloning to

13   produce children,

14   what to think about it, and what to do about it.

15                  This is therefore a useful juncture at

16   which to indicate the distinction, as well as the

17   connection between these two topics.                    Many members of

18   the public, including many of our elected officials

19   who are in the process of making policy in this area,

20   as well as some members of the media, have conflated

21   the issue of stem cell research and the issue of

22   cloning.

23                  The       issue    of    cloning        comes     first      to

24   attention    as     an   issue     of   the      ethics     of   producing

25   children by novel technological means, and the issue
                                                                             7

1    of cloning, insofar as it has captured the public

2    attention, is primarily about what to think about the

3    asexual production of new human beings who are going

4    to   be    genetically      virtually     identical        to    already

5    existing individuals.

6                   And    the    issues there      are    in    the       first

7    instance    the     questions    of    the   ethics    of,        crudely

8    speaking, baby-making.          That is quite different from

9    the question of the ethics of embryo research.

10                  Virtually all embryonic stem cell research

11   now under way, both in humans and in animals, involve

12   cell lines developed from embryos, whether inner-cell

13   mass, or from the gonadal ridge of donated fetuses,

14   that originate from the sexual union of egg and sperm,

15   and very often in the human case using excess embryos

16   produced in in vitro clinics and in all cases from

17   material not produced for the sake of the research.

18   The question of Federal funding of this research that

19   President    Bush    resolved    last     summer,     this       was   the

20   question    that     was    resolved    last    summer,         and    the

21   research in this area proceeds not only with Federal

22   funding     under    the     guidelines      that    the        President

23   established, but also in the private sector.

24                  The    two    topics,    however,     intersect         and

25   overlap      because        cloning     to     produce           children
                                                                         8

1    necessarily proceeds through the production of cloned

2    blastocysts,    which   offer     special      opportunities       for

3    embryonic stem cell and other research.

4                   Some   proposals      to    curtail    cloning      for

5    providing    children   would     do      so   by   curtailing     the

6    initial steps, thus interfering with the possibility

7    of using cloned embryos for research.

8                   And this has given rise to arguments for

9    and against cloning for biomedical research proper.

10   This is where the intersection can be made explicit,

11   and that is where we now are.

12                  In order for us in the other project to

13   continue to make progress, and therefore in order to

14   see what value added might derive from working with

15   embryonic      stem     cells        extracted       from        cloned

16   blastocysts, one needs to know something about what it

17   would be added to. That is to say, to work on ordinary

18   embryonic stem cells. And in order to see more clearly

19   what the ethical issues are that might come from the

20   question of producing cloned embryos for biomedical

21   research, it would be helpful for us to know something

22   of   the    ethical   issues    of     experimenting        on   human

23   embryos of sexual and not clonal origin, and of using

24   extra embryonic -- using the extra embryos or fetuses

25   not created for experimental purposes so we can see
                                                                         9

1    what different questions arise here.

2                   To help us with our scientific and medical

3    education, we are very fortunate to have as our guests

4    and    presenters          this    morning    two    distinguished

5    researchers, one who is a pioneer in isolating and

6    characterizing human pluripotent stem cells, Dr. John

7    Gearhart,     the     C.    Michael    Armstrong     Professor      of

8    Medicine at Johns Hopkins University, and the Director

9    of the Institute of Cell Engineering.

10                  And second a person who is a pioneer in

11   work with human multipotent adult progenitor cells,

12   Dr. Catherine Verfaillie, a Professor of Medicine and

13   Director of the Stem Cell Institute at the University

14   of Minnesota.

15                  Each of our guests in separate sessions

16   will   make   formal       presentations,     roughly     30   to   35

17   minutes, after which time we will have a chance to ask

18   questions     about    the    scientific,     technological,        and

19   clinical aspects of these areas of research.

20                  This    is    our   chance    to   learn   about     the

21   wonderful prospects of these investigations.               However,

22   let me say that because our guests are here not only

23   as scientists, but also as our neighbors, in a morally

24   aspiring human community, we will perhaps try toward
                                                                   10

1    the end to elicit from them their own thoughts about

2    the ethical issues in their own work.

3                   But   the   purpose   of    these   sessions    is

4    primarily our own education about the scientific and

5    medical aspects.       With that I would like to turn the

6    meeting over to Dr. Gearhart, and to thank him very

7    much for joining us this morning.

8                   DR. GEARHART:     I am certainly grateful to

9    have this opportunity to share with the President's

10   Council my knowledge in a very tiny area of biomedical

11   research, and it is currently quite tiny, but if you

12   read and believe the press, it is obviously going to

13   expand enormously.

14                  Much has been written and much has been

15   said about stem cells, and it seems every morning in

16   the paper there is some article relating to it and

17   continuing the debate.

18                  In    the   scientific     literature,   we    see

19   virtually in every issue of leading journals a paper

20   dealing with stem cells.       An age old dream I think of

21   mankind or humankind has been to replace damaged or

22   diseased tissues with functional ones, new ones, and

23   wouldn't it be nice to be able if you had a damaged

24   liver or kidney to take one off the shelf if you know

25   what I mean.
                                                                                11

1                    And this dream I think is going to become

2    a reality, and with some of the advances in biomedical

3    research, and one of the ones that we are going to

4    talk   about    today,      I    think          this   will   provide      the

5    starting material that will lead to this reality.

6                    The concept behind cell-based therapies --

7    and this is what we are talking about here initially -

8    - is a very simple one, and I think that that makes it

9    attractive,     and    it    makes         it    understandable      to    the

10   public.

11                   And that is that if there is a tissue

12   deficit, why not just replace the tissue.                      Now, it is

13   easy to say, and it will be difficult to do, but the

14   concept is an easy one.

15                   Cell-based therapy has also been called

16   regenerative medicine, and there are many rubrics for

17   this today.      The power of this technology is derived

18   from information inherent in our genes and in our

19   cells, and the recent isolation of these embryonic

20   type stem cells I believe is going to provide the

21   enabling    material        as   I    mentioned         for   this    to    go

22   forward.

23                   Stem   cells         are    going      to   serve    several

24   purposes, the first of which could be as a direct

25   source     in   transplantation             therapies.        That    means
                                                                                  12

1    specific cell types will be grown in culture, such as

2    heart muscles, nerves, et cetera, and transplanted to

3    patients for function.

4                    Or they will be genetically engineered to

5    do exactly what we want them to do and transplant it

6    to   patients;       or     they   will     be      used    by     our    tissue

7    engineer colleagues to construct tissues and parts of

8    organs, which would then be transplanted to patients.

9                    Stem cells will also be used as a source

10   of   information,         basic    science,         and    this     is    really

11   where we are at currently. That could be applied to a

12   patient's own cells, such that we could remove cells

13   from a patient and alter them in some fashion to

14   produce   the        cell       types   that     we        want,    and     then

15   transplant them.

16                   Or    ultimately        I feel        that       what we     are

17   going to be able to do from the information that we

18   are going to learn on stem cells is that we will be

19   able to work in vitro with patient cells to get them

20   to perform in a manner that we want without taking

21   them out and putting them in culture.

22                   This,       I    believe,      is    the     future.         The

23   scientific challenges to attain our goal of producing

24   safe and effective therapies are formidable.                             It will

25   take the efforts of many scientists and clinicians, in
                                                                           13

1    a variety of disciplines, to bring this endeavor to

2    fruition.

3                  Now, the stem cells that I am going to

4    talk about today interestingly really do not exist

5    naturally.    That is, they don't exist in embryos or

6    fetuses.    They are artifacts of culture.

7                  But    we    take    tissues      from       embryos    and

8    fetuses and they undergo a type of transformation in

9    culture to provide these stem cells.                 And this source

10   obviously brings with it a number of ethical concerns.

11                 I,    as    an   investigator,         who   has had        to

12   cross this bridge 9 or 10 years ago when I began this

13   work, believe that the ethical issues are manageable.

14                 I     also       believe        that     it     is      the

15   responsibility      of    scientists     to    candidly      and     in    a

16   timely   fashion     present      the   social       implications         of

17   their research and its technological applications; to

18   provide assessments on reliability, and to participate

19   in the establishment of ethical guidelines and to work

20   within those guidelines.

21                 For the past 9 years at Hopkins, we have

22   been in compliance with all institutional, State, and

23   Federal policies in dealing with the cells that we

24   work with.
                                                                                14

1                    It has not been easy because the landscape

2    has changed in 9 years, and every year there have been

3    new concerns raised, and new issues that had to be

4    addressed, and I think we are keeping up with it.

5                    I should tell you also up to this point in

6    time that no Federal monies, no public monies, have

7    gone   into    our    research    effort.             Now   that    Federal

8    policy has changed, we do have applications pending

9    before the National Institutes of Health.

10                   I also want to point out something that

11   may    be   surprising      to   most       of     you;     that    in    our

12   laboratory      at     Hopkins        that       we     just       are    not

13   concentrating on an embryonic or fetal source of stem

14   cells.

15                   We    are   studying        stem      cells    from      adult

16   sources, umbilical sources, et cetera.                        This is the

17   only way that we feel that you can have a scientific

18   advance,      and    that   is   to    be    able      to     compare     and

19   contrast the different sources of stem cells.

20                   So side by side, in the laboratory, in

21   experimental paradigms, we are using stem cells from a

22   variety of sources, and this is what I think has to

23   happen to assess which of these sources are going to

24   prove the most effective for any specific type of

25   therapy.
                                                                             15

1                       Another thing that I want to point out to

2    you is that the work on the human cells, I do have the

3    questions that came from your committee in- hand, and

4    many of them are asking what is the status of certain

5    types of work.

6                       I just want to point out that this work

7    has been ongoing for a period of 2-to-2-1/2 years, and

8    although      we    feel   that      we   are   making     progress,     we

9    certainly are going to come up with, well, I don't

10   know as answer to some of your questions.

11                      I just want to let you know that we don't

12   have all the answers to this, and we are very, very

13   early in all studies of stem cells, be they from the

14   embryonic or adult sources.

15                      I would tell you though that to date the

16   work in our lab and others on embryonic stem cells and

17   the results of that work is certainly consistent with

18   the    idea    that    this     is    going     to   prove    to   be        a

19   productive line of research.

20                      Well,   it   is    interesting     that     very     few

21   people know you and what you are about, and I think it

22   is important to point out something.                 My interests, or

23   my research interests for decades, have been in the

24   area    of     developmental          genetics       and     development

25   biology.
                                                                    16

1                    I     have    been     labeled    as   a     human

2    embryologist, and my interests certainly are in the

3    area of how an embryo goes from a single cell to a

4    multi-cellular integrated organism.

5                    And this is where our research has been in

6    the past 25 years, and I have carried this a step

7    further.        We    are    very    interested   in   congenital

8    malformations and birth defects.

9                    I have had a program project through the

10   NIH for many, many years dealing with Down's Syndrome,

11   and we are very interested in trying to determine what

12   the mechanism is that underlies many of the unusual

13   anatomical neurobiological consequences of this extra

14   chromosome in human beings.

15                   And this is essentially how I got into

16   this work.          We wanted to have in the laboratory a

17   source of cells in addition that we could study at the

18   site or level of the impact of these extra genes.

19                   And this obviously is a goal, along with a

20   number     of        other    genetic-based       diseases    and

21   malformations in the human being.           So this is what led

22   to our getting into this area of research.

23                   Now, I have to say up front that we are

24   now required by our university to reveal where our

25   monies come from, and these are the sponsors of our
                                                                                   17

1    research, and there is one sitting in the middle there

2    that I also have to show to you that I am conflicted.

3                      And which means that to the sponsorship of

4    this    private     company,        we    have      received       money      for

5    research,    for     which      licenses       have      been      negotiated

6    between     Hopkins       and       Geron,       and     that      I     am        a

7    stockholder, albeit a few hundred shares of something

8    that is trading now at -- and I hate to think about

9    it.

10                     It is not in our possession as you know.

11   It is held in escrow.            But nonetheless we do have this

12   arrangement with this company.                   So I would tell you

13   that this is not the motivation, this connection.

14                     Without the sponsorship of this research,

15   this work would not have gone forward over the past

16   seven     years.         We   are        not   in    this    business          as

17   individuals to make money.

18                     Well, having said all of that, let's talk

19   about stem cells.         The first thing I want to give you

20   is a little bit of a primer on stem cells so that we

21   are     talking    the    same      language,          and   you       have    an

22   understanding of where I am coming from.

23                     Well, what is a stem cell, and basically a

24   stem cell is a cell that has two properties.                        It has a

25   property in that it has a capacity for self-renewal,
                                                         18

1    which means that the cell can divide and produce more

2    cells like itself.

3                   And it has some type or some degree of

4    differentiative capability, which means that it can go

5    on to specialize into a single cell type, or it can

6    specialize into a number of cell types.

7                   And in a developmental sense, if we over

8    time at what our research has told us about stem

9    cells, they fall into a number of categories.     Early

10   on in developmental practices, we have a cell that is

11   totipotent.

12                  It can renew, and it can form virtually

13   every cell type that is present in an embryo.        As

14   development proceeds, its developmental capabilities

15   become more restricted until we get into different

16   lineages, specific lineages, and its ability to divide

17   also becomes more diminished over time.

18                  This has been the classical picture of

19   development.     Now, what has happened over the past

20   couple of years interestingly is we find that these

21   restrictions in developmental capability are much more

22   plastic than we had thought.

23                  So out here where we thought that these

24   cells are highly restricted, perhaps they aren't so,

25   and when you remove them from the organism and culture
                                                                        19

1    them, they have capabilities of forming other cell

2    types, and Catherine will be talking to you about some

3    of these issues.

4                    Well, we are going to be talking about

5    embryonic      stem    cells,   and   what   is   it   about    them.

6    Well,   interestingly,      we     know   that    these   cells    are

7    capable of producing virtually every cell type that is

8    present in an embryo, a fetus, or an adult, except

9    one.

10                   And that one happens to be the trophoblast

11   cell, which I will tell you about in a moment.                  So we

12   consider these cells to be totipotent.

13                   They    don't    have the    ability      in and    of

14   themselves to form an embryo or an individual, okay?

15   They have this other property of self-renewal, which

16   basically with respect to embryonic stem cells means

17   that    they     will     expand      indefinitely,       and     grow

18   indefinitely, and this is a very important property.

19                   It means that within the laboratory from a

20   very few cells that you could grow a roomful of these

21   cells very easily.        But there is an issue here that we

22   don't know much about, and that is obviously there is

23   a finite probability that at every cell division that

24   a genetic mutation will appear.
                                                                   20

1                 And there was a paper published recently

2    that indicated that indeed this is the case, and the

3    types of mutation, although the mutation frequency and

4    the mutation rate is greatly -- by several folds lower

5    than in normal somatic cells, mutations do occur in

6    these cells, and they are of the nature of making

7    these cells susceptible to formation of tumors.

8                 The uniparental disomy appears and it is a

9    condition about which we should be concerned.              And up

10   until this point, in the mouse where these cells were

11   first isolated, and for that work the person who did

12   this, Martin Evans, was awarded the Lasker Award last

13   year.

14                We know that these lines forming whole

15   animals, which is what they have been used for up to

16   this    point,   in    genetic       mutations      is     getting

17   genetically defined strains of mice.

18                That there comes a time when these cells

19   are no longer productive in doing this and that they

20   lose some quality.     So we know that there is going to

21   be a half-life to the use of these cell lines for

22   whatever reason.

23                I just want to point that out, although

24   they do have this replicative ability.           Well, where do

25   these   totipotent    cells   come    from,   and    two     major
                                                                 21

1    sources.     The first is this pre-implantation stage

2    which we are going to talk about, and the second are

3    from specific cells within the fetus.

4                 I also have on this slide, and by the way,

5    I have given you two handouts.         One is the slides in

6    the   presentation,   and   another    in   a   fairly   recent

7    Nature review of this material, that you can refer to.

8                 I want to point out another source of a

9    cell that is very similar to these two that we have

10   isolated, and that comes as a stem cell for a specific

11   type of tumor called in the old days teratocarcinoma,

12   and now called mixed cell carcinomas.

13                These stem cells, referred to as embryonal

14   carcinoma cells, were first isolated back in the 1970s

15   when I worked on this, and we thought that these would

16   be the answer to finding cells that would produce a

17   variety of cell types that we could work with within

18   the human.

19                And I should tell you that at this point

20   in time that there is a clinical trial going on at the

21   University   of   Pittsburgh   using   embryonal    carcinoma

22   cells that have been selected for a neural lineage,

23   and so that in culture you can derive neural cells and

24   that these have been placed in the brains of 12 stroke

25   patients.
                                                                        22

1                   It is a cell that is very, very similar to

2    the two that I am going to talk about.                      Well, the

3    first source that you are aware of comes from these

4    structures     here,   which     are    pre-implantation          stage

5    human embryos, and I am sure you are familiar with

6    this.

7                   And where that structure consists of two

8    groups   of      cells;        this     outer       layer        called

9    trophectoderm, and an ectopically placed inner group

10   of cells called the inner-cell mass.                It is from this

11   group of cells here that the embryo proper is derived,

12   and it is connected ultimately to this outer layer,

13   which develops in the placental tissue by connecting

14   stock in an umbilical cord.

15                  These cells may number only 15 or 20 in an

16   embryo that may consist of perhaps several hundred

17   cells.   And in work in the mouse, and subsequently

18   done in humans, first by Jamie Thomson, was that these

19   cells were isolated, placed in a culture condition,

20   which then permits their growth and their conversion

21   into an embryonic stem cell.

22                  This process of conversion can be highly

23   inefficient,    meaning   that        you   would    need    a   large

24   number of blastocyst and inner cell mass cells to

25   derive a few cell lines.
                                                                            23

1                     In some people's hands, it can be more

2    efficient, but there is an issue with that.                    A second

3    source of cells with the same features was identified

4    in the early 1990s, first by Peter Donovan at NCI.

5                     And what they were attempting to do were

6    to culture long term cells that are called primordial

7    germ cells.       These are diploid cells that are present

8    in an early embryo that eventually give rise to egg

9    and sperm.

10                    And    they        isolated,       and       this      is

11   superimposed upon a human fetus, they isolated from

12   the gonads, the gonadal ridges, these large cells,

13   which at the time of isolation in humans are about

14   20,000 of them present in a gonad, and placed them in

15   culture and essentially ended up with the same type of

16   cell.

17                    This   is   what     a human   EG    culture        looks

18   like, this clustering of cells and I want to point out

19   that there are cells in the background here which are

20   the so-called feeder layers.

21                    All of these cell lines are derived on

22   feeder layers, and all the lines that were approved by

23   Mr. Bush, and all the lines that we have, are derived

24   on   a   mouse   feeder      layer,    and   this    is   a   point of

25   contention, meaning that we are concerned now about
                                                           24

1    the fact of any endogenous viruses being transferred

2    from other animal tissues into the human cells.

3                  And the FDA must deal with this at this

4    point in time, but we do not have permission on the

5    use of Federal funds to derive new lines, avoiding

6    this issue of other animal products.

7                  But they are grown on feeder layers.   They

8    are established and grown on feeder layers of other

9    species.    If we compare different properties of these

10   cell types, and I bring this up -- some of these are

11   of no value to you immediately, but these are the

12   criteria that one must use to say whether or not you

13   have a cell line.

14                 It is very important, and of the 80 some

15   lines that are now purported to be available, I can

16   guarantee you in talking to many investigators from

17   around the world that only a handful of these are bona

18   fide cell lines, and/or available to investigators.

19                 Now, this may beg the point and that that

20   may be enough to serve the purposes in the immediate

21   future.    But really the majority, the vast majority of

22   so-called lines available do not meet the criteria

23   that are now used to say whether a line is a line.

24                 Now, how do we -- we are very interested

25   then in two things here.      One is the basic science
                                                                   25

1    aspect of this, and of course what is driving all of

2    this is the hope for some type of transplantation

3    therapy.

4                   Let's    talk   a    minute   about   the    basic

5    science.       What we have in the laboratory now are

6    cultures of cells in the plate that can form any cell

7    type in a human body.

8                   Now, the argument is have we demonstrated

9    that you can get out of these all 200 and some cell

10   types?   No.    You only find what you are looking for.

11                  What    we   have   found   though   are a   large

12   number of cell types that are present in the human

13   body within these dishes.          The problem at the moment

14   is getting homogenous population of pancreatic islet

15   cells or blood cells, or muscle cells.

16                  This is the real part of the scientific

17   struggle here, and coming up with the paradigms to say

18   can we take a cell that can form any cell type, and

19   get it to form but one cell type.

20                  And to do this we have to rely upon our

21   knowledge coming out of molecular embryology as to the

22   genetics and what not involved in any type of cell

23   specialization.

24                  And this is really the limiting issue at

25   this point in time, getting these purified populations
                                                                    26

1    of cells on demand.          There are strategies that are

2    used that we do pretty good at, and we will take the

3    initial populations of cells, and we can change feeder

4    layers, and we can change growth factors, and we can

5    put them in different types of cultures and force them

6    then to begin to specialize.

7                   But they are mixed cultures, and within

8    the    same   dish   you   are   going   to   find   neurons   and

9    muscle, et cetera.         And we must then go another step

10   and begin to sort out either through procedures called

11   flow sorting based on what is on cell surfaces to get

12   then   pure   populations of      hematopoietic      stem   cells,

13   muscle cells, or neuro cells.

14                  And this works fairly well.            We can get

15   cultures of dopanergic neurons that are 80 percent

16   pure, and we can get cardiac muscle that is 97 percent

17   pure, et cetera.

18                  But we are a long way from isolating in a

19   homogeneous fashion the various types of cells that we

20   would like to get.         Some of them were doing well at

21   and others were not.

22                  And it is going to require an extensive

23   amount of research to achieve this.            Now in going to

24   transplantation therapy -- we are going to jump a
                                                                    27

1    little bit ahead here, and if we start, this could be

2    ES.

3                   If we start with this population, we do

4    not transplant into anybody, or into an animal at this

5    point, one of the stem cells.            You don't do it.      The

6    reason that you don't do it is this.

7                   These stem cells are capable of forming a

8    variety of tissues, and they will form tumors, and

9    these tumors are these mixed germ cell tumors that

10   contain a variety of cell types.

11                  They     are    called   teratomas   in   the   old

12   literature.        Monster.    I mean, they are contained in a

13   mixed array, and you can see teeth, sebaceous glands,

14   hair, bone, parts of the gut, et cetera.

15                  So what you have to do to make this work

16   is    you   want    to at     least   get cells   that   you have

17   treated somehow in a dish into some of these more

18   defined lineages that are away from this capacity to

19   form tumors.

20                  So that we then begin to select tissues

21   downstream, all right?           Part of the problem, and you

22   will read this in the literature, is how good your

23   selection is, is also indicated by whether or not when

24   you take myocardiocytes that you say, oh, these are

25   all 100 percent myocardiocytes, you transplant them
                                                                            28

1    into the wall of the heart, and you end up with a

2    teratoma.

3                    This happens, and we are into the central

4    nervous system, and you end up with a teratoma within

5    the brain.      So getting rid of those initial stem cells

6    are   essential,      and    we     have    ways   of     doing    this

7    genetically, but I just want to point out that this is

8    an issue.

9                    To say nothing about the fact that we do

10   not know whether any cell downstream here has the

11   capacity to revert.         We know very little about that at

12   this point in time.

13                   So let me give you an example.              There are

14   many of these coming out in a number of laboratories,

15   most of them in the mouse in which lines have been

16   derived    in   different     lineages,      and   they    have    been

17   transplanted into animals to show proof of concept,

18   and that you can isolate a specific cell type, and you

19   can transplant it, and it will function within the

20   transplant.

21                   I would like to give you now an example

22   from our work at Hopkins.            It is an unpublished work,

23   and   it   is   now   under       review,   but    I    think     it    is

24   important because it really illustrates several points

25   that are critical here.
                                                                        29

1                   We have taken our human cells and grown

2    them under culture conditions that would select for

3    specific types of lineages, and whether it is neural,

4    or whether it is muscle, et cetera.               And now we have,

5    I believe, in our laboratory over a hundred a hundred

6    lines like this, of the human lines.

7                   And in the one example that I want to

8    present to you, which was done with members of our

9    department of neurology, and in collaboration with our

10   lab, is a model, using these cells in an animal model

11   of the motor neuron disease.

12                  And       in   this    study,   these   animals    are

13   treated     with     a    virus      that   destroys   lower     motor

14   neutrons, so that animals become paralyzed, and they

15   are paralyzed because they lose the big nerve muscles

16   that in your spinal cord hook your muscles up to the

17   central nervous system.

18                  So that in a period of 10 days following

19   the injection of the virus into the brain, the animals

20   become paralyzed, and we have gone to great lengths to

21   show that it is really the ventral roots that are

22   involved.

23                  You       wipe   out    these   neurons   and   these

24   animals never recover.            They never recover.      So what

25   we have done is to take our human neural cells out of
                                                                                      30

1    this and infuse it into the spinal cords of these

2    rats, and to look then for the recovery of motor

3    activity.

4                      This          is    a    rat    out    for   a    mid-morning

5    stroll, and this animal is infected with the virus,

6    and     it   is        a     virus         that    really      leads       to     an

7    encephalomyelitis, and within a period of 10 days the

8    animal is paralyzed.

9                      We        can        document         exactly     what        this

10   paralysis is about.                  The virus is cleared, and shortly

11   thereafter    we           will      put    a    cannula    into    the    lumbar

12   region of the animal, and infuse 300,000 cells into

13   the cerebrospinal fluid, and these cells will float

14   all the way up to the hind-brain.

15                     And then we monitor the motor activity of

16   these animals, and within a period of a few months, we

17   begin to see animals that can now place their limbs

18   underneath them, and that can draw them up, support

19   some weight, and begin to push off.

20                     And       at       the   high end,       within     a several

21   month    period,           we     can      have    animals     that    are      now

22   walking.     And the issue is why are they walking.                             And

23   what we have learned, although it is not as you can

24   see a normal gait, et cetera, and we have really

25   documented this as well, they are walking.
                                                                      31

1                  And why are they walking?         Well, initially

2    what we felt was this.        This is a panel showing cells

3    within the ventral horn of those animals and I want

4    you to look at this cell here.

5                  This cell, based on its marker, and based

6    on   its    physical       characteristics,     and     molecular

7    characteristics, is a human motor neutron cell that

8    has been specialized out of these neural precursor

9    cells, that has sent an axon out into the periphery at

10   least two centimeters.

11                 And we have been able to cut the sciatic

12   nerve out on the limb of this animal, place a dye at

13   that site, and that dye is picked up by that axon, and

14   brought back to the cell body that extended the axon.

15                 And it comes back, and this is the green

16   stuff here, and it comes back then into the cell body

17   of   the   human   motor    neuron.     We    have   gone   on    to

18   document how many human cells are present, and what

19   they are as far as the phenotype is concerned, to see

20   -- you know, yes, they are forming glia, and they are

21   forming a variety of cell types within the ventral

22   horn of that animal.

23                 Interestingly,      and   one     of    the   safety

24   issues that we find is that 50 percent of the cells
                                                                          32

1    don't do anything.          And we are a little bit concerned

2    about that.

3                   I mean, is it good to have all these cells

4    in there that aren't doing anything, but this is an

5    issue that we have got to resolve.              Well, it turns out

6    that this is only part of the answer.                 It turns out

7    that the human cells at the same time are producing

8    growth      factors        that     rescue     and    enhance        the

9    regeneration    of     the    animal's   own    cells   within      the

10   ventral horn.

11                  And so this has led us then to set up

12   experiments to try to figure or try to determine what

13   growth factors it is that is causing the growth of

14   axons in those mice and in rats in the ventral horn,

15   and it may be that eventually we can use just the

16   combination of those growth factors to elicit this

17   response.     We don't know.

18                  So     these   cells    are   serving    in    a     dual

19   capacity, which is somewhat exciting.                We have taken

20   the human cells and we now have grafted them into

21   monkeys.    They were in monkeys for over a year.

22                  This was a safety study to in fact show

23   that we are not getting tumors formed.                  I think you

24   can appreciate one of the major issues here that we

25   are   going    to     be    faced    with,   with    this    type     of
                                                            33

1    approach, is animal experiments are of a very short

2    duration.   Mice and rats are for periods of several

3    months.

4                Monkeys we can go much longer.       How much

5    data is going to be needed to convince the FDA that

6    this is a safe approach, and this is something that is

7    being debated now within the FDA and it is a difficult

8    issue.

9                But here we show human cells, and that is

10   these blue ones that have been in this monkey, and in

11   this case for 180 days, but we are now out a year, and

12   we can show that these cells are forming specialized

13   structures and they are non-tumorigenic.

14   The next phase is to look at a graph model here that

15   is functional.

16               DR. KASS:   Can I just ask a question?

17               DR. GEARHART:     Sure.

18               DR. KASS:   What has been injected here?

19               DR. GEARHART:     Oh, I'm sorry.    These are

20   the same -- what has been injected into this monkey

21   are the same cells that were injected into the rat.

22   The same cells.   They were human cells --

23               DR. KASS:   Neural precursors?

24               DR.   GEARHART:     Neural   precursor   cells.

25   The same cells, the same culture cells.      A major issue
                                                                    34

1    that we must discuss and that we are concerned about

2    is graft rejection.      Obviously, anything that you grow

3    up, unless it matches the patient, is going to be

4    subjected to that, and now we get into an area which

5    Dr. Kass has mentioned earlier.

6                    But what are our options here?          What are

7    the options of being able to grow these cells into any

8    of these lineages and then to transplant them and not

9    have rejection?

10                   Well, there is a long list, and it starts

11   with,   well,    maybe   what   we   ought   to   do   is   derive

12   hundreds of ES and EG cell lines, and then you would

13   have a best match for a patient.        Not very practical.

14                   Can we use the patients own cells, and you

15   will hear about some of this shortly.             Should we use

16   immunosuppressive therapies.          We would like to get

17   away from that.

18                   Can we use what the tissue engineers are

19   referring to as sequestering grafts, and what this is,

20   is you can take grafted cells and put around them

21   matrices that will not permit other cells to touch

22   them, but yet they can produce products, or they can

23   function in a graft.
                                                                   35

1                   So you are trying to hide them from the

2    host immune cells.     How effective that is going to be,

3    we don't know.

4                   Can we perhaps come in and genetically

5    modify, which is easy to do in these cells with the

6    histo-compatibility genes, so we can make them more

7    like a patient that is going to receive these cells.

8                   Or is it possible that we may end up being

9    able to produce cells that may be universal donors.

10   Again, we are trying this, and at the moment it is

11   speculation.

12                  Clearly the one thing that has worked is

13   the issue of nuclear transfer therapy, the so-called

14   therapeutic cloning, in which as you know the argument

15   is to take a cell from a patient, and fuse it to an

16   enucleated egg, derive a blastocyst, recover the inner

17   cell mass, culture it out, and then these embryonic

18   stem cells would match the genome of the patient.

19                  Is this a pipe dream?       The answer is no,

20   and I will give you an example of that in a moment.

21   To   get   around   some   of   the   issues   with   the   human

22   cloning, embryonic cloning in humans, you have seen

23   reports in the Wall Street Journal and other places

24   which I can confirm are real, in which there are

25   attempts now to take human cells, human nuclei, place
                                                                        36

1    them for example into rabbit eggs, enucleated rabbit

2    eggs, and grow up a blastocyst, and generate stem

3    cells that have human nuclei and rabbit mitochondria.

4                     And the argument has been made here that,

5    well,    these    cells   would    be   perfectly    fine    for    an

6    autograft, and this isn't accurate.                 We know that

7    mitochondria produced polypeptides that are integrated

8    into the cell membrane, and are actually considered to

9    be   minor   histocompatibility         antigens,   and     will    be

10   recognized and rejected by the host from which the

11   nucleus came from.

12                    So this really is not getting around the

13   issue of the graft stuff at all using other animals,

14   and we are a little bit concerned about how this is

15   being handled.

16                    So, let me give you an example, and one

17   which you should read these papers if you haven't from

18   Rudy    Jaenisch    and   George   Daley    at   MIT,   using      the

19   nuclear transfer therapy, or the therapeutic cloning,

20   to do two things.

21                    What they did was to take a mouse that had

22   a genetic mutation in genes that are important as far

23   as the immune response is concerned.                And they took

24   cells from this mouse, took the nucleus out of the
                                                                           37

1    cell, and placed that nucleus into an enucleated egg

2    to produce a blastocyst from a cloned embryo.

3                    They took the inner-cell mass cells out of

4    that, and generated embryonic stem cells, that then

5    are the same genome type as this animal, and then went

6    in and repaired genetically the mutation within those

7    cells.

8                    And then differentiated these cells into

9    the   hematopoietic       stem    cell    component,       transferred

10   them back into this animal that had the mutation, and

11   the      transplant       took,      completing        the          whole

12   hematopoietic system, and in rescuing that animal.

13                   So this is a proof of concept kind of

14   experiment, and I urge you to read it.                      It is an

15   extremely      powerful    illustration,      not     only    of     the

16   therapeutic     cloning     end    of     things,    but     also    the

17   ability then to come along and correct the genetic

18   mutation and the reference was given to you.

19                   Another argument has been made that we

20   should    be   using   perhaps     just    eggs     that    have    been

21   stimulated to form embryos, and these are parthenotes.

22                   And the argument here has been that we can

23   then use these directly into the female from which the

24   eggs were taken.       I just want to point out that in my

25   opinion that this is going to have very low usage.
                                                                                38

1                    You are going to have to recover embryos

2    or     eggs   from     patients,         post-pubertal,            and    pre-

3    menopause.      The window is going to be fairly short, I

4    think, for many of the therapies that you would want

5    to effect.

6                    And the other issue is that we don't know

7    much about cells that are derived this way, and how

8    viable, and how functional they are going to be.                          But

9    this has been used or promoted also as a source, and

10   this is an illustration of where you take those cells.

11                   All of this type of technology, I just

12   want    to    let    you   know,        and    I    know    that    you   are

13   grappling with this, but even within the field of the

14   scientists are beginning to argue about what is an

15   embryo and what isn't an embryo.

16                   So any arguments that you have within your

17   council on this, I will tell you is also being held

18   among    biologists.          I    think       that    my   own     personal

19   feeling is that anything that you construct at this

20   point    in    time    that       has    the       properties      of    those

21   structures to me is an embryo, and we should not be

22   changing vocabulary at this point in time.                      It doesn't

23   change some of the ethical issues involved.

24                   What are some of the problems here, and I

25   will summarize this a little bit.                     Current research.
                                                                      39

1    Well, we have to come up with better ways of having

2    high efficiency differentiation protocols resulting in

3    homogeneous cell populations.

4                We are dealing with growth environments,

5    and genetic manipulations, and we are trying to define

6    stages of cell differentiation within our cultures.

7                And     assessing         whether      or     not    the

8    differentiated    cells     that    we    are   getting    out   are

9    normal and completely functional.               And this is in a

10   dish.

11               And     let   me    tell      you    that   there    are

12   examples of where you can spend all of an effort

13   studying something in a dish, only to find that if you

14   pop it in an animal that it doesn't behave how you

15   think it is going to behave.             We have a lot to learn

16   here.

17               I think you can imagine that what is going

18   on in a dish is not exactly what is going on in a site

19   where you transplant.          The whole issue of grafting,

20   and how you put it in, and the safety issues, and that

21   cells migrate away, and they differentiate, and will

22   they form tumors, and then the issue of the immune

23   response.

24               These     are      all,      you    know,   formidable

25   obstacles that lie ahead.          I mentioned to you that we
                                                            40

1    can use cells individually, and have been used in a

2    variety of paradigms in our collaborators of single

3    cells, and the tissue engineers are now taking these

4    different   cell   types   and   seeing    if   they   can

5    reconstruct or construct organal aids or tissues to do

6    in-grafting, and thee has been some success with this

7    at this point.

8                Finally, to me, the future is going to be

9    that the basic science coming out of this is the most

10   important element, and that from that information we

11   are going to be able, I think, to take patient cells,

12   where appropriate, and I say where appropriate because

13   if you have autoimmune disease, or in cases where you

14   have an injury, spinal cord injury, or stroke, or

15   heart attack, and you don't have time to take that

16   patient's cells, you are going to have to come up with

17   different paradigms.

18               But I think we are going to be able to

19   eventually coax a patient's own cells to behave in a

20   manner that we want to, but we are going to learn this

21   I think through the study of stem cells.

22               The last thing I will say is I know that

23   you want to ask, well, what is the future going to

24   bring, and I am concerned about predicting the future.
                                                          41

1    I can't even do this on a three year NIH grant and

2    this is what is expected of us.

3                You know, what is going to happen here. I

4    certainly think that everything that has happened up

5    to this point is consistent with success in this area,

6    and I could get into more predictions in a moment.

7                But we are always asked when is this going

8    to happen, and it is going to be I think based on

9    specific cell types, and on, and on, and on.     But the

10   predictive thing is very, very difficult.

11               Well, I thank you for your attention, and

12   I hope that this was enough of a primer to add more

13   meat to your discussions.    Thank you.

14               DR. KASS:   Thank you very much.

15               (Applause.)

16               DR. KASS:     We were only physically in the

17   dark, but we are grateful for your enlightenment, Dr.

18   Gearhart, and the floor is open for questions, and

19   comment, and discussion.     Don't forget that you have

20   to turn your microphones on to be heard.        Jim, go

21   ahead.

22               PROFESSOR WILSON:     Dr. Gearhart, do you

23   foresee that it will ever make a difference whether

24   cells that are transferred for human cell regeneration
                                                           42

1    come from cloned eggs, or from the retrieval from IVF

2    eggs?   Does it make a difference what the source is?

3                 DR. GEARHART:   Well, I think in the short

4    term that it will.       I think the only way we have

5    around the immune rejection story at this point is

6    from cloned embryos.

7                 For a patient in which you can predict

8    ahead of time is going to need stem cell therapy and

9    you have the time and money available to do the cloned

10   approach.

11                I would like to think that this is going

12   to be a transitionary period, and that we will not

13   have to rely upon this in the long term, and that we

14   will be able to take for any specific disease a stem

15   cell, or a derivative of a stem cell that may come

16   from the adult source, the umbilical source, the fetal

17   source, or embryonic source.

18                I mean, whichever presents, and that we

19   will have ways of dealing with this graft rejection

20   story other than through the cloning of human embryos.

21                PROFESSOR   WILSON:    If   I   could   just

22   supplement my question with a related one to which you

23   referred.    What is your current assessment of the

24   value of adult stem cells, as opposed to embryonic

25   ones, as a source of organ regeneration currently?
                                                                                        43

1                     DR. GEARHART:                Oh, I think it is a very

2    viable option and I think NIH should fund it.                               I think

3    that from what we see in the work, and Catherine will

4    present a nice overview of this, that this is going to

5    be a good source of stem cells.

6                     They have some issues that they have to

7    overcome,       issues          of    expandability,           and    plasticity,

8    that we feel are -- that have not been demonstrated as

9    well    as    embryonic              stem    cells,      but    I     think       that

10   eventually we will be able to overcome this.

11                    But        I    think      part    of    the        knowledge      of

12   overcoming it is going to be coming from our studies

13   of cells that have those capabilities, and being able

14   to transfer that information to those other cells.

15                    So I think we are going to come up with --

16   I     believe        that       in     the       stem    cells,           cell-based

17   therapies, that we are going to identify certain adult

18   sources that are going to be good for some diseases,

19   some injuries, and embryonic sources for others.

20                    So       I     think       we   are     going       to    mutually

21   proceed on this and benefit from it.

22                    DR. KASS:             Please, Elizabeth.

23                    PROFESSOR BLACKBURN:                    Dr. Gearhart, you

24   can    give     us    I     think      a    unique      perspective          on    the
                                                                        44

1    comparison    between      adult,   and embryonic,        and    fetal

2    stem cells.

3                   And   in    particular      many    of   us read   the

4    recent   papers,     the    scientific      peer-reviewed       papers

5    that came out with respect to the adult stem cells,

6    and the interpretation of their plasticity being cast

7    in some considerable doubt by the observation that

8    there was cellular fusion of those cells which had led

9    to in these particular cases examined a mistake in

10   interpretation of their plasticity.

11                  And I wondered if you could give us your

12   perspective    on    that     aspect,      which    extends     Jim's

13   question somewhat.

14                  DR. GEARHART:        I will do so in the face of

15   Catherine sitting back here, who is --

16                  PROFESSOR BLACKBURN:          Yes, I am going to

17   ask her, of course, about this, too.

18                  DR.   GEARHART:        --    actually     done    those

19   experiments.     Clearly the most difficult experiments

20   that we have had to address and interpret are those

21   utilizing adult stem cells that have been placed into

22   the blastocyst of mice to create chimeras.

23                  And in those chimeras, we see that the

24   descendants of those adult cells gave rise to many,
                                                                              45

1    many lineages within the embryo, and this was really

2    the issue.     How did we explain this.

3                   And from the studies of Austin Smith and

4    others that you are referring to, the implication was

5    that    when   those     cells    were    transplanted        into      that

6    blastocyst to generate the chimeras, that a subset of

7    these cells fused with the hosts own cells and it was

8    those    fusion    products       then   that     gave    rise     to    the

9    variety of lineages.

10                  At the moment that is an implication, and

11   that has not been demonstrated in the embryo.                      It has

12   been    demonstrated      in     the   dish     that   they   had       that

13   capacity.

14                  So we are now waiting and putting pressure

15   on Catherine, and Freizen, and others to look into

16   those    animals    to    see     if     they    can     recover     those

17   specialized cells that were derived from or that had

18   the adult phenotype if you know what I mean, the

19   marker, to say are you truly of the adult stem cell

20   lineage, or do you have other markers present, other

21   chromosomes present, that come from host cells.

22                  So until we see that data -- you know, I

23   will wait.        That is something that can be looked at

24   scientifically, and that is as far as I would go with

25   you, Elizabeth, at this point.
                                                                         46

1                 It is an interesting observation, and we

2    will see if it actually is the answer.

3                 PROFESSOR BLACKBURN:            And just to extend

4    on what you said, I think what it does now do is to

5    demand that the onus be put on the researcher to show

6    that     there     has     been        a       plasticity            or

7    transdifferentiation,     and   there        are    other     set    of

8    criteria, which would be karyotype and multiple micro-

9    satellite,   polymorphisms      --   sorry         to   get    overly

10   technical -- and other genetic markers.

11                There are clearly tools in hand, and so it

12   seems as if every experiment can in fact be subjected

13   to those sets of analyses now.

14                DR. GEARHART:      Right.

15                PROFESSOR BLACKBURN:          And will need to be

16   before we can get a good view of this.

17                DR. GEARHART:      Right.

18                DR. KASS:    Rebecca.

19                PROFESSOR DRESSER:        I have four questions,

20   and maybe if I say them all it will be possible to

21   answer some of them together.        One, I was wondering if

22   the rats are being given immunosuppressants in this

23   study.

24                And   then   you   said     a    problem       with    the

25   rabbit eggs is that the mitochondrial DNA might cause
                                                                             47

1    rejection, and so I wondered if that would happen with

2    a cloned human embryo as well if the egg came from

3    another person, and if you are trying to do a therapy

4    that is compatible with a patient.

5                       And let's see.       The feeder layers, I was

6    wondering if they have available feeder layers that do

7    not    come    from    animals    or    what    the    state    of     that

8    development is.

9                       And then finally what about the fact that

10   if you are creating a blastocyst from a patient's

11   cell, and if the patient, let's say, has cancer or

12   some    condition      that    could    be   related     to    genetics,

13   would the stem cells somehow perhaps be risky?

14                      DR. GEARHART:       There is no question in my

15   mind that the possibility exists that if you are doing

16   an egg donor, and nuclear transfer into an egg, that

17   there       possibly   exists    that    that    cell    --    that     the

18   embryonic       stem   cells     derived       from   that     could     be

19   rejected.       Absolutely.

20                      Now, how do you test this?           I mean, where

21   do you test it.           This almost comes under the same

22   criteria that I have for anyone coming to -- if I was

23   on     an    IRB    and   they     wanted       to    clone    a     human

24   reproductivity, what data do you present before you

25   permit it to go.
                                                                              48

1                   To me, it is one of these things where you

2    need    perfection     before      experimentation,           or    without

3    experimentation,       which       is    something      in   science      is

4    anathema.

5                   PROFESSOR DRESSER:            Well, you could test

6    that in an animal, right?               I mean, you could at least

7    see --

8                   DR. GEARHART:            Well, you can, and we could

9    set it up in an animal, but the issue is -- I mean,

10   where you are very defined and to demonstrate it by

11   doing it into a different strain of mouse.                         There is

12   no question about it.

13                  But whether or not that would carry over

14   in polymorphisms that exist in human, again you are

15   still faced with human versus rodent.

16                  The feeder layer issue.              It is one that is

17   being taken on, and there is no banning of this type

18   of work with private money, and clearly there are a

19   number    of   investigators,           laboratories,        working      on

20   establishing     feeder      layers       from    human      tissue     that

21   could    be    used,   and     I    think        that   this       is   very

22   important.

23                  So those studies are certainly under way.

24   We have used a variety of different human tissues as
                                                                49

1    well to look at in our studies.          Oh, the very first

2    question that you asked.     I'm sorry, it was again?

3                 PROFESSOR DRESSER:       For the rats --

4                 DR. GEARHART:    Oh, sorry.     We did animals

5    that were immunosuppressed and animals that were not

6    immunosuppressed.   And we did not find a great deal of

7    difference in the short term, although -- I mean, as

8    far as any type of destruction of cells and things

9    like that, although clearly in the animals that were

10   not immunosuppressed that you could see reactive cells

11   present.

12                So     clearly       in        the         monkeys

13   immunosuppressed, absolutely, and so we have done them

14   both.   And then the blastocyst question?

15                PROFESSOR DRESSER:        If it comes from a

16   patient with a particular disease.

17                DR. GEARHART:     Yes.     Clearly where there

18   is a genetic basis of any type of a disease, you would

19   be concerned about reintroducing the same cells that

20   were subjected to whatever the disease process was.

21                And I think that this carries over also

22   into, for example, the diabetes work, where if you

23   have an attack on insulin itself, you know, is this

24   going to be a viable alternative, and there are some

25   evidence now that you can alter the insulin molecule
                                                                 50

1    to make it not recognized by some of the autoimmune

2    antibodies.

3                  I should say that there are a number of

4    laboratories -- and this is one area that is being

5    emphasized in the use of human cells, including our

6    own, with Mike Shamblott, where we have lines that are

7    -- human lines that are insulin producing that you can

8    pop them into animals, and demonstrate that they can

9    produce human insulin.

10                 And    we   are   very encouraged   by some    of

11   these early results.        But I would still contend that

12   we have a long way to go to carry that into some type

13   of clinical application.         We have a lot of questions

14   to answer.

15                 DR. KASS:     Janet.

16                 DR. ROWLEY:       Well, I, too, have multiple

17   questions and I want to thank you for a very lucid

18   presentation.       That helps a great deal. I would like

19   to first -- and I think I will do these one at a time.

20                 It is a substantial question as to what

21   value the embryos that are left over from IVF can play

22   in this whole process as compared with embryos that

23   you develop for either a particular purpose, or just

24   straight off.
                                                        51

1                And my understanding was that maybe some

2    of the embryos were sufficiently mature so that maybe

3    the cells derived from IVF would not be useful in

4    developing, say, cells lines or things.   And I would

5    like your comments.

6                DR. GEARHART:   One of my hats at Hopkins

7    when I moved there in the late '70s was to develop the

8    IVF program.   So we are very well tuned into the

9    issues of IVF, and clearly in an IVF procedure the

10   best embryos obtained are those that are used first in

11   first transfers.

12               So that generally those that are left over

13   are of the ones -- we don't want to call it a lesser

14   quality, but at least as far as our eye is concerned,

15   and how we judge grades of embryos, based mainly on

16   morphology to be honest, and more currently we are

17   looking at biochemical parameters that we can measure

18   in the media in which these cells are growing that

19   something has been secreted to have some kind of a

20   measure.

21               And that clearly those that are the spare

22   embryos generally are those of -- let's say, what we

23   deem, and knowing what that means, of lesser quality.

24               So what does that mean?    In most cases,

25   they have not developed far enough along, which means
                                                                              52

1    that if they are left over that you take them back out

2    of the freezer, and you try in your culture conditions

3    to get them up to this blastocyst point.

4                     If    you   can't       get   them    to   a    blastocyst

5    stage, you can't derive the cells.                      If there is no

6    inner cell mass, you can't do it.                     And you find that

7    you are compromised there, and that generally these

8    are not very good embryos.

9                     So one could argue that overall that you

10   would    expect       to   have    a   low     efficiency       yield   with

11   respect to taking in embryo and deriving a line from

12   spare embryos in an IVF program.                 That is in general.

13                    DR.       ROWLEY:         Okay.         You     mentioned

14   modifying the histocompatibility locus, and I would

15   have thought that there is still so much that we don't

16   know     about    the      MAC    that    that     would    --    I     mean,

17   obviously anything can be done in the future with

18   time, but do you look on this as practical?

19                    DR. GEARHART:           Well, back in the ancient

20   days, in the early '80s it seems in this field, Oliver

21   Smithies and others did do knockouts of Class I and

22   Class II genes, in an effort to determine whether or

23   not this could prolong grafts into animals without

24   those.
                                                                      53

1                    And that depending on the tissue or the

2    organ, there was evidence that this indeed could be

3    the case, and not that it was an indeterminate thing,

4    but just by days, or weeks, or months, that this was

5    the case.

6                    What they didn't know about at that time

7    were NK killer cells, and those kinds of things, and

8    the importance of other determinants which must be on

9    cells.   They wiped everything out.

10                   So some labs are now taking a look at this

11   to see if it is possible then to rebuild back some of

12   these markets.      But it is a matter of speculation at

13   this point whether or not this could occur.

14                   Now, what we can talk about I think is it

15   possible to take using the act of transgenesis and

16   things like this, where we could move big pieces of

17   DNA; of taking part of a patient's chromosome-6, you

18   know, and cloning that into a stem cell after knocking

19   out some of it, and we may get some degree closer.

20                   But that says nothing about the myriad of

21   other    loci     that    could      be   involved     as    minor

22   histocompatibility       problems.        So,   some   of   it    is

23   speculation, but I think it is also testable at this

24   point in time.
                                                                        54

1                    DR.   ROWLEY:       And    my   last    question    is

2    coming back to the 80 plus cell lines, and you raised

3    concerns, which many of us have, as to how useful some

4    of those are going to be.

5                    DR. GEARHART:       Right.

6                    DR. ROWLEY:         Could you expand a little

7    bit, in terms of whether you think they are really not

8    going to be long term cell lines, and that is your

9    concern, or whether there are other aspects.

10                   DR. GEARHART:       Well, I have many concerns,

11   and I hope that I can get them all in.                 I mean, look,

12   we were all thrilled when Mr. Bush made the decision

13   to move forward with this and establish cell lines to

14   permit the work to go forward.               There is no question

15   about it.

16                   But as we looked into -- and by looking

17   into, it was a practical matter.                Many investigators

18   around    the   world,   and    I   have     close   contacts   with

19   colleagues in Germany, and in France, and in England,

20   and Japan, and Australia, and on and on, as we compare

21   notes all the time on our results of research, as well

22   as on practical things like this, and on political

23   issues.

24                   I mean, there is no question that we have

25   to keep abreast, and what happened, particularly from
                                                                      55

1    the German investigators, which is significant, as you

2    know, in Germany, they are not permitted to derive

3    cell lines.

4                  And for a while they were not permitted to

5    use those that were even derived, and recently their

6    parliament voted to permit the use of existing cell

7    lines as of January 2002.

8                  But     what   happened    was    that    when   these

9    investigators       set   about   to   import    cell   lines,   and

10   contacted     the    registry     list    at    the     NIH,   which

11   continues to grow each day, and more lines are added

12   to it as you know, it turned out that many of the

13   lines were not defined.

14                 Someone      just   reported      that    they   had    a

15   clump of cells growing in a dish, and they didn't have

16   any of these parameters or very few of them done.

17                 And this reduced the list substantially,

18   quite substantially, down to -- we are talking about,

19   say, a dozen.       And then the issue came up as to, well,

20   are these -- can they be imported without a stringent

21   material transfer agreement, and with a reach through

22   clause that would say that anything that you would do

23   with those lines belongs to the person giving you the

24   line.
                                                                     56

1                  And this reduced the line substantially.

2    And then other lines are not available because if you

3    needed to get them, you needed NIH funding, and only

4    NIH funding.      You could not use private funding with

5    them, and on and on.

6                  And so it drastically reduced down the

7    number of lines that are practically available.                Now,

8    whether or not this will have a major impact, clearly

9    the   NIH    is   receiving   grants,        and   we   have   been

10   reviewing    grants,   and    using    the      existing   approved

11   lines, the few that one can get.

12                 And the work will go forward, and whether

13   or not that will be sufficient, and we recognize that

14   there is going to be a half-life to these lines for

15   various reasons, and that there will come a time if it

16   proves effective in the basic science part of this to

17   move forward, that we should be looking at being able

18   to generate new lines.

19                 And the issue of the feeder cells is a

20   major issue as well, and to begin to establish lines

21   on human cells so that we are not faced with that

22   anything that we derive from this now, and it is

23   important    to   consider,   has     to   be    considered    as    a

24   xenograft.
                                                                      57

1                   Although    it   is   a   human    line,    the   FDA

2    requires that if it has seen these other products, it

3    has to be considered a xenograft, which sets up a

4    whole new set of criteria for moving this into the

5    clinical applications.

6                   So I think there are reasons why we should

7    eventually be permitted to derive new lines.                  Well,

8    I'm sorry.      We can do it now on private money, but

9    anything that is derived cannot receive Federal money

10   for support.

11                  DR. KASS:        There are people waiting in

12   line, but can I get a clarification on this question

13   that   came   up   in   your    answer     to   Janet   about    the

14   durability and longevity of the lines, and on the one

15   hand, one says that the embryonic stem cell lines,

16   their great virtue is that they can be self-renewed

17   indefinitely.

18                  On the other hand, they have a half-life,

19   perhaps because of accumulated mutations.                 Could you

20   say a little more?        I mean, some people claim these

21   are eternal lines.

22                  DR. GEARHART:      Right.

23                  DR. KASS:        And could you say something

24   about the possible differences between human and mouse
                                                                       58

1    with respect to renewability, because I think it is an

2    important factor.

3                   DR. GEARHART:         Well, the issue is maybe

4    they are eternal, but can you still use them.                    They

5    can still divide indefinitely, but they may not --

6                   DR. KASS:       But they are no longer the

7    same.

8                   DR. GEARHART:        Yes, they are no longer the

9    same,   and    they    may    not     give     you    the   biologic

10   properties that you need.             Strangely enough, Leon,

11   there   have   been    very   few    publications      up   to   this

12   point, and up to this point there is one that I can

13   cite for you, and I have it in answer to some of your

14   questions by Joe Stanbrook at -- Peter Stanbrook, at

15   the University of Cincinnati, in which he looked --

16   these were mouse lines.

17                  And he looked at the frequency and rate of

18   mutation within several mouse lines, and contrasted

19   those with several schematic cell lines that were in

20   the lab as well.

21                  And    he   found    that     indeed   the   mutation

22   rates -- and what you do is you pick certain genes to

23   look at changes, and to look at chromosome lost or

24   gain.
                                                                          59

1                       This paper was published in PNAS in the

2    March 19th issue for those who are interested, and

3    what he found was that the frequency and rates of

4    mutation      were     orders      of    magnitude    less    in     the

5    embryonic stem cell line than in the schematic cell

6    line.

7                       And you are looking at a rate of generally

8    10 to the minus 6 frequency within any mammalian cell

9    as it is divided.          But what he did find, and that was

10   a bit troublesome, was that the type of mutation that

11   appeared in the embryonic stem cell one led to what is

12   called uniparental disomy, which is a situation where

13   you    end    up    with   homozygosity      across   a    region,    or

14   across chromosomes          or    regions of       chromosomes, that

15   gets    rid    of    really      the    dominant   tumor   suppressor

16   genes, which then raises the issue that these cells

17   may be more susceptible to tumorigenesis than others.

18                      Now, that is the only report, and I will

19   tell you that in several laboratories what is being

20   done now with the human lines, and that is using

21   express sequence tags, for example, and you can use

22   10,000 of them, they are looking at mutation rates at

23   10,000 loci, if you know what I mean, over time in

24   culture passage, after passage, after passage.
                                                                                      60

1                     So   we     will       get     information                on   this

2    parameter, and how significant it is going to be, I

3    don't know, but one would predict that clearly there

4    is going to be an accumulation of mutations within

5    these cells.

6                     DR. KASS:            Okay.         Thank you.               I have

7    Michael -- well, also, was that on this point?

8                     PROFESSOR BLACKBURN:                 Just a very brief

9    clarification.             Did        the     absolute          frequency         of

10   uniparental      disomy      go       up?        Was       it        an    absolute

11   frequency     increase,          or     simply       did        it        relatively

12   increase    as    you      looked       at    the    whole           spectrum     of

13   mutations in the mouse embryonic stem cells?

14                    Do you see the difference that I am trying

15   to get at?

16                    DR. GEARHART:          Yes.

17                    PROFESSOR BLACKBURN:                That if it were an

18   absolute increase, that is a reason for concern, much

19   more than if it were simply a relative increase in a

20   number that has already gone down by --

21                    DR. GEARHART:               These numbers are rates,

22   and so I believe it is an actual number.                                   In other

23   words, it was a real --

24                    PROFESSOR            BLACKBURN:                An          absolute

25   increase?
                                                               61

1                DR. GEARHART:      Yes, an absolute increase.

2                PROFESSOR BLACKBURN:        So I just wanted to

3    make sure that I understood the numbers here.

4                DR. KASS:   Michael Sandel, and then Frank.

5                PROFESSOR SANDEL:        I would like to go back

6    to the adult stem cell versus embryonic stem cell

7    question, and ask it in a slightly different, and

8    maybe more pointed, form.

9                As you know, there are some people who

10   regard   embryonic   stem     cell    research   as   morally

11   objectionable.   I am not asking you or trying to drag

12   you into that debate.       But I would like to know your

13   view on the following scientific question.

14               If adult stem cell research in the best

15   case scenario redeems its promise, what would we lose

16   medically and scientifically if we ban embryonic stem

17   cell research, or imposed a moratorium on it for a

18   period of time, until we could assess what adult stem

19   cell research could achieve?

20               DR. GEARHART:      I personally think it would

21   be a tragedy, and for the following reason, if this

22   was to happen.   I think the length of time that it is

23   going to take to assess whether the adult stem cell

24   avenue is going to provide the potential therapies

25   that we are thinking about, is going to be years.
                                                                 62

1                 And I think for us to deny at this point

2    any avenue that has the potential of the embryonic

3    stem cell story is a tragedy to those people who need

4    or who will need these cures.

5                 And I think that it is a time element.          If

6    this could be done in a year, I would maybe listen to

7    that argument.      But it is going to take years to

8    really assess any of these approaches.

9                 And    I   really   think   they    should    move

10   forward together.       I think we are going to learn in

11   both directions how to utilize information coming out

12   of these studies that would benefit, for example, or

13   enable us to understand more about the adult sources

14   if this is going to be the emphasis, and to really

15   make them effective in their use.

16                So I think that it wouldn't be wise to put

17   a ban on the embryonic source at this point, and wait

18   until another avenue is assessed.        The length of time

19   is going to be too long.

20                PROFESSOR     SANDEL:       Can    you   be   more

21   specific?   Are there certain types of research avenues

22   that you would associate more with embryonic stem cell

23   research, as against adult stem cell research?

24                Is it likely that success is in particular

25   areas, or is it just that you feel that as a general
                                                                            63

1    matter it is better to have more avenues rather than

2    fewer?

3                   DR. GEARHART:            Well, I think that one of

4    the messages that I hope that I can get across, and

5    maybe Catherine will, too, is that we are in very

6    early stages in all of stem cell research, no matter

7    what the origin of the cells are.

8                   And to make a judgment as to which of

9    these is already more advanced than the other, it

10   would be a tenuous one at this point, because you have

11   got to remember that there are very few investigators

12   actually    working    on    embryonic         stem      cells   at   this

13   point.

14                  The list on the adult side obviously is

15   larger.       I    mean,     as        far   as    investigators       are

16   concerned.        And I don't think that any of us are

17   really showing dramatic -- you know, utilization in

18   the sense that we can say we are going to go to any

19   clinical use of this.

20                  It is going to take years for this to

21   occur.     We are in the very early stages and so I would

22   be   really       hesitant        to     say      that     anything     is

23   demonstrating anything better.

24                  All I would say about embryonic stem cells

25   at this point in a very positive way is that we know
                                                                           64

1    that at this point that out of these cells we can

2    virtually generate any cell type we want in dish and

3    in large numbers.

4                 That is the advantage of this approach.

5    Now,   whether     this    will       be   surmounted         by    other

6    discoveries in adult stem cells to do the same kinds

7    of things, I don't want to predict.                   I hope that it

8    happens.

9                 You       know,    our   --   and    I    also    want    to

10   emphasize that we -- and although we are associated

11   with the embryonic form, we are studying other forms

12   as well.   We are not foolish.

13                As    a    scientist, you       know,      you are       not

14   going to put all your eggs in one basket here.                     And so

15   we are trying to move forward on a broad front, and I

16   think that this would be the more rational way to

17   proceed in this arena.

18                DR. KASS:         Frank.

19                PROFESSOR FUKUYAMA:             Dr. Gearhart, did I

20   understand you correctly that in the experiment that

21   you headed up with the mouse that it lost the motor

22   function in its rear legs, that you were injecting

23   human stem cells?

24                DR. GEARHART:            Yes.       Well, if I could

25   correct you a moment.          It was a rat, first of all.
                                                                   65

1                 PROFESSOR FUKUYAMA:       Okay.    A rat.

2                 DR. GEARHART:      Rat, too, but the issue is

3    please don't say that you are injecting stem cells.

4    These are derivatives of stem cells.           I mean, just so

5    that we know, but they are out of the stem cell line,

6    okay?

7                 PROFESSOR FUKUYAMA:        Okay.      Fine.     But

8    what was the resulting tissue?        It was a mixture then

9    of rat and human neurons, or do you think it was

10   simply the stimulation of these other factors that was

11   causing the rat neurons?

12                DR. GEARHART:       Right.        That is a good

13   question.   We still don't know -- I mean, to be honest

14   with you -- what the mechanism of recovery here is.

15   We know that sitting in the ventral horns of these

16   animals, and where these big neutrons reside, you now

17   have a mosaic population of host cells, of neurons,

18   inner-neutrons.

19                I mean, we all -- I mean, human and rat,

20   or human and mouse, depending on which one we did.             We

21   don't know the relative contributions.           We can count

22   cells, but really what is the functional basis of what

23   occurred there.

24                We   know   that   the   human    cells   are   also

25   rescuing the other, but to what degree.          This is where
                                                                         66

1    the hard work comes in.              What was the mechanism, and

2    what really went on or is going on in that ventral

3    horn.

4                 I can tell you in work that John McDonald

5    has done at Wash U, in which they generate a contusion

6    injury in the spinal cord of a mouse or a rat, and

7    then infuse in mouse embryonic stem cell derivatives,

8    and that he is faced with the same issue.                  He can see

9    that these animals recover to a certain degree, but

10   the   mechanism    of       what   is   it,   of    what   has   really

11   occurred there, is not known.

12                And I think what we are going to find is a

13   demand that we come up with mechanism in some of these

14   animal models so that we can completely understand

15   what that therapy is going to be if you take it to a

16   human.

17                And this is going to require a lot of

18   work.    Now, some of it you could argue is that you

19   could do it all within animal studies.                      You know,

20   mouse embryonic stem cells, and you don't have to put

21   the human in.

22                But        I    think      we    are    finding     enough

23   differences between species that it would warrant at

24   least the study also of the human derived cells in the

25   same paradigms to ask those questions.
                                                                             67

1                      PROFESSOR   FUKUYAMA:             But    I     am   just

2    curious.      Are you getting actual tissues in which you

3    have cells from different species that are growing

4    simultaneously?

5                      DR. GEARHART:      Oh, yes, absolutely.             Yes,

6    sitting     in    the same    --   well,      you    can   see    in the

7    section here that might be 15 or 20 microns across,

8    you see a mixture of the rat cells or mouse cells, and

9    human cells, functioning.

10                     You know -- I mean, this isn't uncommon.

11   We    do   interspecific      grafts      a   lot    in    experimental

12   things, and the question is when you do it, and we

13   see, you know, human cells growing in animals very

14   nicely.      I mean, as long as there is immunosuppression

15   and things like this occurring.

16                     PROFESSOR FUKUYAMA:         But could you go the

17   other      way,   also   injecting        stem   cells     from       other

18   species into human beings?

19                     DR. GEARHART:      Oh, yes.        I mean, this is

20   one of the issues with xenografts.                  You know, is this

21   something -- well, there is a report recently about

22   chicken embryonic stem cells, and the fact that people

23   who   had    derived     these     were    promoting       the    use    in

24   humans.
                                                                68

1                 Pig stem cells, you know, et cetera, and

2    so it can be done, but a couple of issues, and one of

3    them is the issue of the xenograft itself, of bringing

4    in endogenous viruses, and is this a wise thing to do.

5                 And the other thing that I would ask you,

6    and I won't be flippant about it, is to say that if

7    you -- and one of the concerns that we have that maybe

8    this council and others would take up, is long term in

9    a neurologic sense.

10                If you are putting stem cells in, and you

11   are putting them in between different human beings,

12   what are you doing to that individual.          And I would

13   say to you that if you have a stroke, and someone

14   comes along and says, well, we have pig, cow, mouse,

15   human, take your pick, what would you select.

16                I am not being flippant about it, but I am

17   just saying that I think that we know that human would

18   be preferable at this point in time.

19                DR. KASS:       Could I ask a question, and

20   just   for   clarification     again    also   on   your   own

21   experiment that you showed us.         You said that some of

22   the rats were immunosuppressed and some were not.           Is

23   that correct?

24                DR. GEARHART:     Yes.
                                                                       69

1                    DR.    KASS:       And    were   there    functional

2    differences in the results between those two groups,

3    and would that bear upon the question of whether or

4    not the major effect was owing to the action of the

5    human cells, or a stipulation of the endogenous cells?

6                    And lastly, if these animals had come to

7    post-mortem     was     there   a    difference?          Was   there

8    rejection in the non-immunosuppressed animals of the

9    human cells?

10                   DR. GEARHART:       It is important to keep in

11   mind the time frame that these experiments are done

12   in.     They    are    of   very    short      duration   relatively

13   speaking, in a period of several months maximum.

14                   In experiments that have been done in our

15   laboratory, principally by Mike Shamblott, in taking

16   human   cells    and    grafting,        and   these   are   insulin-

17   producing cells, and we have done it in a variety of

18   tissues into rodents, you always see reactive cells,

19   which means that you are eliciting an immune response.

20                   Again, they are short term, and whether

21   you are getting destruction, we see cellular debris,

22   and we see this kind of stuff at these sites.                          I

23   should tell you a little bit that may be enlightening.

24                   When you do grafts like this, if we say we

25   are putting in 300,000 cells or we are microinjecting
                                                                 70

1    in a lot of these cells, many of these cells will die

2    at the time of injection, simply because you have

3    taken them out of one environment and you put them

4    into another, and you see a tremendous amount of cell

5    death.

6                  Very few of these populations of cells

7    continue to divide.       In other words, it may undergo

8    one more round of division, and they sit there.

9                  You do see when you come in finally to

10   look at where is the human versus where is the rodent,

11   and you use your human markers.     You invariably find a

12   group of cells that you can't phenotype, if you know

13   what I mean, and to say what has happened here, and

14   clearly there are cells being destroyed.

15                 DR. KASS:   Fused?

16                 DR. GEARHART:    Well, we don't know that.

17   And one of the arguments for many years has been that

18   the central nervous system is an immune privileged

19   site.    I don't think anymore that this is something

20   that is believed or subscribed to, and if you have the

21   option   of   immunosuppression,   or     of   getting   around

22   that, that that would be preferred.

23                 And   particularly   when    you   are     talking

24   about a graft going into a human being that may be

25   there for 20 years, as opposed to a matter of a few
                                                                           71

1    months.     So I think that this is going to remain a

2    major issue, and there is no question about it.

3                     DR. KASS:         Thank you very much.              Bill

4    Hurlbut and then Paul McHugh.

5                     DR. HURLBUT:       John, I hear you saying that

6    we should pursue all lines of research, but I want to

7    weigh     the    different       options    here     and   pursue     the

8    question of if the lines were restricted what would be

9    gained or lost.

10                    Specifically,       I     have    several    questions

11   that hinge each on the other.              First of all, the cells

12   that were implanted or tested for their tumorigenicity

13   effect that you spoke of in your paper were the so-

14   called EBDs.

15                    Were    those    derived     only    from    embryonic

16   germ cells; is that what is implied there?

17                    DR. GEARHART:       Yes.    In our paper, we took

18   the stem cell itself and plated it out in a variety of

19   culture    conditions,       some    of    which     are   designed    to

20   enhance         or      select      for      certain         types     of

21   differentiation.

22                    And we referred to these as embryoid body-

23   derived cells.          They came out of this little cluster,

24   and in our field it is essential that we take the stem

25   cell off the dish, and let it form into a little ball,
                                                           72

1    and which is just a multi-cellular structure, called

2    an embryoid body.

3                  Now, this was an unfortunate name that was

4    given to it by a French pathologist back in the '30s,

5    but as you can imagine, when someone in a political

6    sense talks about an embryoid body, they conjure up

7    embryos here.

8                  But these are little clusters of cells,

9    and within those or within that cluster, the beginning

10   of   differentiation     begins.       These   cell-cell

11   interactions are essential for this.    We have not been

12   able to mimic this in a sheep yet.

13                 So what happens is you get within that

14   ball a variety of cell types being formed, and all

15   that you want to do is to disassociate that ball after

16   a period of time, and select out only those that are

17   going in the direction that you want them to go in.

18                 So this is what we did in that experiment,

19   and so we have now these EBD lines, and in these

20   lines, in these human lines, and these lines have been

21   placed in a large number of animals, in the grafts

22   that we have used, we have never seen a tumor up to

23   this point.

24                 And it may be unique to humans, because

25   human primary cultures are easy to establish and mouse
                                                                      73

1    aren't.       I mean, there is an issue here that we don't

2    know that you can't do the same experiment in the

3    mouse.

4                    So with our experience with the EBDs, we

5    have never seen a tumor.         Our experience in the mouse

6    and using what we thought were equivalent lines, we

7    have seen too many tumors with respect to grafts into

8    the central nervous system.

9                    DR. HURLBUT:    Just parenthetically haven't

10   I been reading all along that embryoid bodies are also

11   formed from ES cells?

12                   DR. GEARHART:    Oh, yes, absolutely.

13                   DR. HURLBUT:     But the point is that your

14   particular lines don't produce tumors, and the ones

15   derived from the primordial germ cells don't seem to

16   produce tumors; whereas, the embryonic stem cell lines

17   do?

18                   DR. GEARHART:        Well, the only comparison

19   that we have at this point are mouse ES lines, in

20   which we have derived different types of precursors

21   under    different     conditions,     have    been   compared    to

22   human    EG    lines   that   have    been    derived,   or   which

23   precursors have been derived in a slightly different

24   manner.
                                                                              74

1                     You can't derive them both in the same

2    way.     We have seen nothing up to this point on human

3    ES derived lines transplanted.                   We just have not seen

4    any data on that.

5                     So I don't want to make it clear that

6    there is a difference between the derivation either

7    from    a   germ      cell    derived,      or    an    inner-cell      mass

8    derived line.          Does that make sense?             That comparison

9    is not there yet.

10                    DR. HURLBUT:         Well, obviously what I have

11   been getting at here is if in fact your cell lines are

12   less likely to cause tumors, then does that imply that

13   there    might       be    some    advantage      to    using   your    cell

14   lines, and if so, would it in fact be the greatest

15   advantage       if    a    patient's    own      cell    line    could    be

16   derived from primordial germ cells?

17                    DR. GEARHART:             Oh, boy, this committee

18   would -- well, wow.               Now, think what this means.             It

19   means that you would be generating an embryo, and

20   having it implanted.              Now, what you don't know is that

21   our     fetal    tissue       comes    from       5-to-9    weeks      post-

22   fertilization.            These are therapeutic abortions.

23                    And       which   means    now    that    you    are    way

24   beyond -- I mean, the point of where a blastocyst is,
                                                                    75

1    and obviously way beyond I think anyone subscribing to

2    that approach.

3                 DR. HURLBUT:        You told us that in your

4    paper.

5                 DR. GEARHART:       Okay.

6                 DR. HURLBUT:        But is it true that maybe

7    there would be some great advantage if we could find a

8    legitimate way to harvest tissues generated from a

9    specific patient at a later date?

10                DR. GEARHART:        Right.      Well, I think it

11   would be terribly risky.          We have been asked this

12   question a lot though; is it possible to do a biopsy

13   on a developing embryo, and to remove just a few germ

14   cells.

15                I think at the stage that we are using

16   these embryos are a matter of -- or fetuses are a

17   matter of maybe 6 or 7 millimeters in length, and to

18   do   the   surgery   on   this    I   think    would   just     be

19   impossible without causing harm.

20                The other issue that I would contend is do

21   you think it would be okay to go in and remove the

22   germ cells from an embryo and let that individual go

23   on and say, well, we have taken your germ cells.              Now,

24   we have another therapy for you.

25   And so I don't think it is a very good thing to do.
                                                                           76

1                  DR. HURLBUT:        And that is my final point,

2    and I wanted to ask you personally in working with

3    these cells, do you see 14 days as some kind of magic

4    marker moment?

5                  Do     you    see    something       crucial          about

6    implantation?       And you spoke of keeping all options

7    open.

8                  DR. GEARHART:       Right.

9                  DR. HURLBUT:         Why in fact do we allow

10   abortion fairly late in term, and yet now we are

11   speaking as 14 days as the sacred moment?                I know that

12   I am opening a very difficult issue here.

13                 But    in    fact    wouldn't       we    gain    a    lot

14   scientifically      from    extending      that    14     day       limit

15   potentially if we could find a culture median that

16   could sustain the embryo, or wouldn't we gain a lot

17   from implanting, even gestating and harvesting?

18                 And why do we feel that we shouldn't do

19   those things?       And I would also be interested in your

20   personal response to these ethical issues.

21                 DR. GEARHART:       Wow, you have asked a lot.

22   As you know, stem cells have been obtained from many

23   stages of human fetal development, and have been found

24   to   be   useful    in   generating   various      cell    types       in

25   culture.
                                                             77

1                   And if we look at a variety of studies,

2    you can find it in the published literature.      We have

3    had a number of requests for fetal tissue at different

4    stages,      and   I   think   legitimate   requests     of

5    investigators willing to investigate cell lineages, et

6    cetera, within the embryo.

7                   So people have been thinking about it.        I

8    mean, there is no question about that.      We have found

9    it difficult enough to be fortunate enough to obtain

10   the fetal tissue that we work with.

11                  I mean, there is a consenting process and

12   we have nothing really to do with other than to make

13   sure that it complies with institutional, Federal, and

14   State law.

15                  To obtain viable tissue from abortuses of

16   any kind is a major concern.        When we started our

17   studies, we looked into using spontaneously aborted

18   material, which occurs across the board, but mainly in

19   the early stages.

20                  And we thought that this would be a good

21   source.   As it turned out, by the time that we were

22   notified -- and this occurs in outlying hospitals, and

23   not at major medical centers, where investigators are

24   -- you know, a patient presents with a miscarriage,

25   and it is taken care of in the ER.
                                                                      78

1                  And    it    turned      out   that   it    was   very

2    ineffective, number one.         And, number two, and then I

3    will get back to your question, we found that most of

4    the   material    that    did   come    to   us   had    chromosomal

5    abnormalities that made it less desirable for use.

6                  Now, the issue of the 14 days, and what

7    does it mean.       Well, this was something that really

8    came into play in the United Kingdom when they were

9    trying to deal with this issue.

10                 And it was decided at that point that at

11   that stage the embryo still does not have a central

12   nervous system.      It can feel no pain, et cetera.             And

13   this was why basically that period of time was set to

14   be able to grow them in culture, or to remove tissue.

15                 We, as embryologists, argue the point all

16   the time as to what is going on in these early stages,

17   and we were always asked these questions.                When do you

18   believe personhood occurs and when is it established,

19   and things like this.

20                 To me that is not a biologic question.              We

21   don't have a means of probing that.               So I think that

22   is why the 14 days was selected, and that's why it is

23   sort of adhered to in a sense.

24                 Do I adhere to that?           Well, to a certain

25   degree, no.      We take material that is later on, and it
                                                               79

1    is cadaveric fetal tissue.      I think that we should be

2    able to utilize any tissue that comes out of abortion

3    if the alternative is that it is just going to be

4    disposed of, which is what happens.

5                   The pathologist takes a look at it to make

6    sure that all of the parts are accounted for, and

7    there is an issue about being concerned about what is

8    left in the uterus.

9                   That is my personal opinion on that.      But

10   I don't think that we should be going and establishing

11   pregnancies,    and   to   downstream   then   utilize   that

12   tissue.

13                  I mean, to then stop the pregnancy and

14   then to recover it.        I mean, that is my personal

15   opinion.   I don't think we should be doing that.          As

16   you know, years ago, President Reagan was faced with

17   this, I believe, when he heard that families were

18   establishing pregnancies so that regions of the brain

19   could be harvested to treat Parkinson's disease in the

20   family.

21                  And clearly we don't subscribe to that in

22   any fashion.

23                  DR. KASS:   Thank you.   We are coming up to

24   the break and I have Paul McHugh, Mike Gazzaniga, and

25   we are running a little late because we started a
                                                                    80

1    little late.     We will take a break shortly.            Paul and

2    then Mike.

3                   DR. MCHUGH:    My point is very brief, John,

4    because you have touched upon it in several places.

5    But first of all, I want to thank you very much for

6    that coherent presentation, and I especially thank you

7    for showing us experimental data.

8                   And   that    is    what     of   course   generates

9    better questions to ask you.              And it is really out of

10   that experimental work that I did have a question.

11   And that is what you showed us was fundamentally a

12   xenograftic     experiment        using     human   tissue,   human

13   cells, in rats.

14                  And the results were very interesting, and

15   not only was there growth of cells, but you told us

16   that there were trophic factors that were probably

17   acting in this way.

18                  And I then wondered, and you can answer

19   this, why was it necessary to use human cells to

20   demonstrate this phenomenon in a rat, and why weren't

21   you using rat cells to do rat experiments.

22                  And if that is true, that you could do rat

23   cells to do rat things and the like, the development

24   of the question is would it not be wise of us to ask

25   you all to go back and work with your rats and your
                                                            81

1    mice, and your cats and your sheep, and keep going at

2    it, and come back and tell us why you need human stuff

3    to do this stuff, okay?

4                   DR. GEARHART:   Okay.   We did it first with

5    mouse cells.     We don't have rat embryonic stem cells.

6    We did it first with the mouse and it worked.

7                   And in our exuberance, saying, well, would

8    the human cells work, and they did.           There is no

9    question that I think that the mouse cells worked

10   better, and the mouse cells were from these neural

11   precursors that we had obtained that I had mentioned

12   that we had this concern about tumors.

13                  But they did work, and so the only two

14   cell types that we have found at this point that work

15   have very similar origins if you know what I mean.

16                  Clearly the paradigm has to be extended to

17   other sources of stem cells, adult and umbilical, and

18   this is planned to say in this particular paradigm

19   will it work.

20                  So, Paul, the answer is that we did it

21   first with the rodent cells, and we could pursue that.

22   I mean, as far as looking for the growth factors and

23   what not.

24                  But we have changed almost completely to

25   the human cells for trying to determine what those
                                                                     82

1    growth factors were that were secreted, but we could

2    do that again with the mouse, absolutely.

3                   DR. KASS:    Mike.

4

5                   DR.   GAZZANIGA:     Just   briefly,    thank    you

6    again for a wonderful presentation.              This moves to

7    another level, and that is how big is the American

8    biomedical engine.

9                   And I ask that from the sense of having

10   just taken a trip to China and Japan, and England, and

11   you read that Sweden and Singapore, and India, and so

12   forth, are going ahead.

13                  If America dropped out of this for legal

14   reasons that are on the horizon, how big an impact

15   would   that    have   on    the     overall    resolution     and

16   development of these therapies?

17                  In other words, if you just look across

18   molecular genetics and microbiology now, and prior to

19   this issue arising, what is the size and importance of

20   the American effort?

21                  DR. GEARHART:        Well, I don't think that

22   there is any question that the investigators funded

23   through the National Institutes of Health, and our

24   academic   establishments      here,   are     the   engine    that
                                                                          83

1    drives biologic research, biomedical research, in the

2    world.

3                      There is no question about it.                 I mean,

4    the volume, the sheer volume of this, is enormous.

5    And    if   you   look at      this    compared      to   even   in our

6    country to what the biomedical industry, or I mean the

7    private industry is putting into this, it is dwarfed

8    by the Federal funding.

9                      And this is really what is enabling and

10   this is why I think the U.S. has been so far ahead.

11   So it is essential I think to have Federal funding

12   into this area really to reach our goals as quickly as

13   possible.

14                     There is one last thing or one thing that

15   I   would      like   to say   to     the    committee,    and    it is

16   understandable, but when you are in and start in a

17   business like this, you don't know the impact of it.

18                     The thousands of communications that we

19   have received from patients, and patient-based groups,

20   about our work and about moving the work along, not

21   only is it emotional, it is unbelievable.                        I mean,

22   from     the    standpoint     of     just    pure    numbers,     sheer

23   numbers.

24                     It doesn't just extend within the United

25   States, but throughout the world.                    In 1998 when we
                                                           84

1    published our paper, within a few days we had 10,000

2    e-mails alone about it.

3                 And every day I still get hundreds of e-

4    mails relating to this.    It extends not only to bona

5    fide -- you know, many people don't understand what

6    this work is about.

7                 They are contacting you for a brain, or a

8    uterus, or from some countries we have had requests,

9    hundreds of requests for penises, for example.        And

10   you are trying to figure out why -- you know, what is

11   the issue here.

12                We need education and we need informing to

13   say that we are dealing really with cells and tissues

14   at this point.    That is what we are really about.    It

15   is going to be years away before it goes beyond that.

16                And so what I am trying to say is that

17   there are requests throughout the world.    So that is

18   one issue.   I mean, the pressure is enormous, and also

19   people offering you large sums of money to provide

20   them with cells outside of the arena that it should be

21   done in.   Do you know what I mean?

22                There is desperation, and you see this,

23   and it is tragic, and as a researcher this is new to

24   you.   This is something that you are not accustomed to

25   and never will be accustomed to handling.
                                                             85

1                  So I just wanted to let you know what that

2    pressure is like.    It is enormous.     I have boxes full

3    of these things.     I don't know what I am going to do

4    with them, but you try to respond.

5                  There has been an issue with brain drain.

6    We know that there has been one investigator from the

7    University of California system that went to the U.K.

8    and received one-and-a-half million pounds to pursue

9    this work in the U.K.

10                 Well, this happened here.      I will tell you

11   that -- and I am talking to students in our own group,

12   you know, go to Europe for your post-doc, and go to

13   England for your post-doc if you want to continue in

14   this thing.

15                 And I think you will see more of this, and

16   whether major investigators will leave, I don't think

17   so.   I think we will get through this, and I hope that

18   we will get through this period in this country.

19                 There are many, many investigators, many

20   investigators, and I can't tell you what it is like

21   not to be able to give a cell to the person next door

22   to you because of a policy.

23                 I   mean,   this   is   just   an   incredible

24   situation.    I think we will get through it, and I

25   think we will be okay.     But I am still concerned about
                                                                               86

1    it.      Sorry    for the         editorial, but      I    think     it    is

2    important.

3                     DR. KASS:         Charles, did you want a quick

4    word?

5                     DR. KRAUTHAMMER:           If I could just ask a

6    very quick question.              You said that you would oppose

7    and you supported the opposition of creating a fetus

8    for, say, harvesting the brain cells, and you talked

9    about the example in the Reagan years.

10                    On the other hand, there is no difficulty,

11   at least in your estimation, of using tissue from a

12   discarded      fetus       already      aborted,   and     tissue     which

13   would otherwise be thrown away.

14                    Would you apply that same distinction to

15   the embryonic stage?              In other words, you now use --

16   you     develop       embryonic      stem    cells    from     discarded

17   embryos from IVF clinics, and would you be equally

18   opposed to the creation of embryos specifically for

19   their    use     as    sources     of    embryos     using    that    same

20   analogy?

21                    DR. GEARHART:          No, I would not be opposed

22   to that.       I don't give the same moral status to that

23   entity.

24                    DR. KASS:         Well, we have -- let me just

25   make    mention       of    one    matter.         Janet     Rowley       has
                                                                       87

1    submitted   in     writing,    and   I   would     endorse,    these

2    questions if we had enough time.

3                  We would like your comments on what kind

4    of    regulation    you   think      might    be   or   should     be

5    developed for this area, and what is the status of

6    government support for what kind of research, and what

7    are the limitations that are counterproductive.

8                  If we could invite -- if you would be

9    willing, and these are hard questions and they are big

10   questions, but if you would be willing to respond if

11   we put these set of questions to you, and perhaps some

12   others to you in a letter?

13                 DR. GEARHART:        Absolutely.

14                 DR. KASS:       I think the committee would be

15   very grateful for your help in thinking through the

16   regulatory questions, which are at the moment not what

17   we have here.

18                 DR. GEARHART:        Absolutely.

19                 DR. KASS:       I just want to thank you very,

20   very much, for an instructive morning, and also for

21   the   wonderful    spirit     in   which     you   presented     your

22   remarks and engaged the questions.            I am very grateful

23   to you for coming.

24                 We are running about 15 minutes behind,

25   and we will reconvene at a quarter-of.                  We have an
                                                               88

1    hour-and-a-half for the second session this morning as

2    originally planned.

3                (Whereupon, at 10:33 a.m., the council was

4    recessed and resumed at 10:49 a.m.)

5                DR. KASS:    Would the members please rejoin

6    the meeting.    While we are waiting in the hope that

7    our straggling colleagues will arrive, a couple of

8    matters of business.

9                If anyone has not turned in a request for

10   a box lunch, please do so now, and that should be in

11   front of you.     We will have lunch in the room just

12   down the hall where we gathered before.

13               The photographer who has been around here

14   is doing individual photographs for the commission and

15   he will want to take individual photos of members, and

16   we can do that in connection with lunch.

17               And you will also have in front of you in

18   addition to the materials that Dr. Gearhart provided

19   us, which by the way is -- and the lights were out and

20   so you couldn't see, but one could recapitulate his

21   talk with the help of the figures here, as well as

22   checking his article in Nature.

23               But   you   also   have   in   front   of   you    a

24   revised version of Bill Hurlbut's memorandum.            This

25   has been updated and corrected, and he would like us
                                                                  89

1    to substitute it for the one that was sent around

2    earlier this week.    Is that correct, Bill?

3                  DR. HURLBUT:     Yes.

4                  DR. KASS:   All right.       Well, again, it is

5    a great pleasure to welcome Dr. Catherine Verfaillie,

6    from   the   University   of   Minnesota.      You    have   her

7    curriculum vitae in the briefing book, which you can

8    consult.

9                  I won't waste any more of her time by

10   reading from it, and just simply allow her to help

11   educate us on the prospects of present and projected

12   of adult stem cells for regenerative medicine.

13

14                 DR. VERFAILLIE:         Good morning.    I would

15   also like to start out and thank Dr. Kass and the

16   council to allow me to present this information on new

17   findings in adult stem cell biology which have been

18   received with great excitement, and correctly so. If

19   they are, and they are actually set upside down, the

20   classical paradigms of biology, and so to be able to

21   do that you have to have full proof to actually be
22
23   able to be in a position like that.
24

25                 If they are, and they are actually set

26   upside down, the classical paradigms of biology, and
                                                                   90

1    so to be able to do that you have to have full proof

2    to actually be able to be in a position like that.

3                  As   Dr.    Gearhart     already   gave    in   his

4    previous eloquent description of what stem cells are

5    and what they can do, and we will get back to that to

6    some extent at the end, although we are far away from

7    actually   being   able    to    use   adult   stem   cells   for

8    clinical applications.

9                  But what I would like to do is give you an

10   overview of the greater potential of adult stem cells,

11   which   has   always      been    termed   adult      stem    cell

12   plasticity, and what we do know and what we don't

13   know.

14                 And where this may actually lead us.            Dr.

15   Gearhart also indicated that embryonic stem cells in

16   humans are fairly or very much in their infancy, the

17   same as we are for adult stem cell biology, too, and

18   so I don't think we are anywhere close to be able to

19   come up with new therapies at this point in time.

20                 I would also like to reiterate that even

21   though my laboratory and our group works on adult stem

22   cells, we have actually actively pursued investigators

23   in embryonic stem cell research, human embryonic stem

24   cells, just so that within the same institution we

25   would have laboratories that have one cell, and other
                                                                    91

1    laboratories that have the other cell, so we would be

2    in a position to compare and contrast the potential of

3    the different cell populations, and I think that is

4    very important.

5                 With    that,     I    will    actually   start    my

6    presentation, and I will point out that the work was

7    mainly funded through the NIH, since it is all adult

8    stems that we are working on, and not embryonic stems.

9    And   also   a      number     of     foundations      and     one

10   pharmaceutical company.

11                Dr. Gearhart already gave you an overview

12   of where embryonic stem cells come from, and where

13   primordial germ cells or stems come from.              And I am

14   going to reiterate that for you.

15                I    just   put   up    this    cartoon   that    Dr.

16   Weissman published two years ago in Science to point

17   out a couple of things.        During development, cells in

18   the inner cell mass make sequential decisions, and

19   each of these decisions is actually accompanied with

20   gain of function, but also loss of function.

21                The gain of function is that the cells

22   learn how to become a more specified cell type; and on

23   the other hand, actually lose the potential to become

24   other cell types.
                                                                            92

1            And so the decision to be made is somatic or

2    germ   cell,    and      within      the     somatic    lineage    doing

3    something that is called gastrulation, cells decide to

4    become the different parts of our body, whether it is

5    endoderm,    which       is   the    internal       organs,    mesoderm,

6    which are limbs and soft tissue, and ectoderm, which

7    really comprise the skin, the central and peripheral

8    nervous system.

9                   And    within        each   of   these    groups    cells

10   again make decisions and learn how to become stem

11   cells for specific organs.                 And the stem cells for

12   specific organs that has been most well studied is

13   actually     the     hematopoietic           stem    cell,     which    is

14   currently      extensively           being      used    in      clinical

15   applications       for    bone      marrow      transplantations        or

16   peripheral blood stem cell transplantations, or cord

17   blood transplantations.

18                  And so that actually has set the paradigm

19   on how we decide what stem cells are.                         Aside from

20   hematopoietic stem cells or blood stem cells, we have

21   a number of investigators who have identified tissue-

22   specific stem cells in a number of different organs,

23   including for instance the brain, which we until about

24   10 or 20 years ago thought was a final product when we

25   were born.
                                                                 93

1                   But it is now clear that there are stem

2    cells in the brain that can recreate neurons and other

3    components.     There is also stem cells in the liver,

4    and stem cells in the gut, and there is stem cells in

5    the skin, and so forth.

6                   The reason why I put this slide up is

7    actually to point out that these arrows have always

8    gone down, and so we have always thought that each

9    time a cell decided to learn something new that it

10   lost the capability of doing something else.

11                  And so if we envisioned beforehand that

12   the arrows would be reversed, we thought that was

13   possible,     but   we   associated   that   with     classical

14   transformation, or actually cancer-forming cells.

15                  So what do we know about hematopoietic

16   stem cells and that is really the paradigm to which I

17   am going to try to talk through the whole field of

18   adult stem cells.

19                  In   hematopoietic     stem   cells,    we   can

20   actually take a single mouse bone marrow cell that we

21   characterize by proteins on the cell surface, and take

22   that single cell, and for instance you can take it

23   from a mouse that is engineered to fluoresce green

24   under a specific light, and put that in a regular
                                                                             94

1    mouse, and ask whether they can reconstitute the blood

2    elements of that animal.

3                   And      a     number          of    investigators      have

4    actually been able to do that.                     You can take a single

5    cell,    and   give     it    to     a    mouse      that    was   lethally

6    irradiated so it has no blood, and this cell can

7    recreate the red cells, the white cells, platelets,

8    lymphocytes, for the lifetime of that animal.

9                   And that is really the proof that you have

10   a stem cell that can self-renew, and a single cell can

11   make multiple different things, and it can repopulate

12   functionally the organ that it needs to repopulate.

13                  And so that is really the criteria that we

14   have to hold ourselves to, to actually talk about stem

15   cells, and if you talk about plasticity, you will have

16   to hold us on the same criteria and showing that a

17   single cell can now make two tissues, and that this

18   cell can make two tissues from a single cell, and that

19   these new cells can repopulate a tissue functionally

20   in vitro.

21                  Now, over the last 5 or 6 years, there has

22   been    an   enormous       number       --   well,    not    an   enormous

23   number, but probably 40 or 50 papers now that have

24   come out in the scientific publications that have used

25   the word adult stem cell plasticity.
                                                                     95

1                   And what is meant by that is that you take

2    a cell that was supposed to be a one cell type.                For

3    instance, you take a bone marrow cell, or you take

4    cells that are enriched for hematopoietic stem cells.

5                   And it appears that some of these cells

6    may acquire characteristics of cells outside of the

7    organ where they came from.            And so it has been shown

8    for   bone    marrow      cells,   or     cells   enriched     for

9    hematopoietic cells, that if you transplant these into

10   an animal that was irradiated, and you look in tissues

11   outside of the blood, that you can actually find, for

12   instance, skeletal-muscle cells, heart muscle cells,

13   or endothelial cells, that are now derived from this

14   donor hematopoietic cell.

15                  There is also papers that have shown that

16   if you take muscle from an animal and mix it up in the

17   laboratory, and culture it for a few days, and then

18   use the muscle tissue to give back to an animal, that

19   you   could    reconstitute     the     blood   system   in    that

20   animal.

21                  Now, if you think in anatomical terms,

22   this is still within one of the three categories that

23   I gave you at the beginning; mesoderm, endoderm, and

24   ectoderm,     and   all    of   this     is   still   within    the

25   mesoderm.     So this is maybe not so hard to understand.
                                                                                 96

1                     However, there is also papers that two

2    different cells from bone marrow, hematopoietic cells,

3    and zymogenic cells, which are cells that make bone

4    and cartilage, can give rise to cells that appear to

5    have neuronal characteristics, both neurons and glial

6    cells, that support the structure of the brain.

7                     And there is a number of studies that have

8    shown that bone marrow cells can contribute to liver,

9    skin, lung, gut, and so forth, and so you can pretty

10   much put arrows in whichever way you want.

11                    You know, people have published data that

12   suggests      that      indeed    this     may    be     possible.           So

13   obviously this goes against our paradigms and this

14   would say that either something strange is going on,

15   and just something in the last few years is something

16   that we have actually identified.

17                    Now, if we want to talk about blastocyst,

18   I started out with the paradigm of stem cells, and so

19   there is multiple different possibilities here.

20                    Either the bone marrow, which seems to be

21   the   organ      that    harbors     the     most       of   these    cells,

22   harbors    many,        many     different       stem    cells,      and     it

23   harbors    the    hematopoietic          stem    cells,      but     it    also

24   harbors the neuro stem cell, and the liver stem cell,

25   and so forth.
                                                        97

1                And which that would not be bad, but that

2    truly would not be a single stem cell that could be

3    expanded and used to actually transplant patients with

4    all kinds of different organ diseases.

5                A second possibility is that somehow the

6    cell can be "de-differentiated" and redifferentiated,

7    depending on the environment that it is put in, and

8    that the hematopoietic stem cell can learn how to

9    become a liver if you put it in the liver, or it can

10   learn how to become a brain if you put it in the

11   brain.

12               Or it could be that it is a remnant of

13   embryonic stem cells or the primordial germ cells that

14   you heard about from Dr. Gearhart that are left around

15   in the body, and that under specific circumstances can

16   be reactivated and contribute to tissues.

17               And the issue of fusion has been brought

18   up because of the two papers recently in Nature, and

19   the possibility is in theory that what we see is

20   actually that.

21               For instance, a hematopoietic stem cell

22   fuses with a liver cell, and now you actually have

23   something that is a hybrid, but it has actually liver

24   characteristics.
                                                                               98

1                     The other questions that I am going to try

2    to address, and I don't have all the answers for this,

3    is this actually clinically relevant?                       You know, if

4    you transplant bone marrow into a patient and you find

5    two liver cells that are derived from the patient,

6    from the donor, it doesn't necessarily mean that that

7    is going to help anybody down the line.

8                     So     the     graft    has     to    be    robust       and

9    persistent, and there has to really be proved that we

10   don't just see cells that look like a tissue that they

11   end up in, but they also have to function like a

12   tissue that they end up in.

13                    And then the question that I will bring

14   back   up   at    the    end,     the    first    question,        what    is

15   plasticity,      and     will    that    matter       from    a    clinical

16   standpoint?

17                    And so we started out in this field -- I

18   am     a    hematologist,          and     I      do        bone     marrow

19   transplantation as my clinical profession, and I have

20   been interested in hematopoietic stems in the bone

21   marrow.

22                    And about six years ago somebody in our

23   group asked me whether we could grow mesenchymal stem

24   cells, which are cells that may grow on cartilage, to
                                                                     99

1    treat children with a specific genetic disease called

2    Hurler's disease.

3                    And when we did this, mesenchymal stems we

4    happened to find, and we went about trying to create

5    these to be in compliance with GMP qualifications,

6    meaning we were trying to remove all sera out of the

7    system,   and    yet   we   were   trying   to   use   very    well

8    defined culture systems.

9                    And so while we were doing this, we came

10   up with a cell that you have heard Dr. Kass refer to

11   as a multi-potent adult progenitor cell, because we

12   don't have a much better word for it.

13                   And it will be appreciated as MAPC, and

14   which appears to have a much greater possibilities

15   than the mesenchymal stem cell possibilities.                 So we

16   take these cells from bone marrow from humans, and we

17   can also take them from mice and from rats.

18                   And you place these in a culture system

19   that is very well defined, and ingredients, and growth

20   factors, and no serum, and low density, and we expand

21   the cells as much as we can by splitting the cultures

22   on a regular basis.

23                   And if we do this, we have actually found

24   that these cells appear to have an enormous growth

25   potential.      And so here on the left-hand side would be
                                                            100

1    bone marrow from an individual, and we start with

2    about 10cc's or a spoon of bone marrow, deplete all

3    the blood elements from the bone marrow, and put it in

4    a culture dish, and then grow the cells for long

5    periods of time.

6                  Classical adult cells would actually not

7    expand much more than 50 times or 60 cell population

8    doublings, just because we have a clock inside the

9    cell   that   actually   causes   the   cells   to   become

10   senescent or old once they go beyond a certain number

11   of cell divisions.

12                 And so in the human system, as well as in

13   the mouse and the rat system, we have been able to

14   show that we can create or grow cells that do not seem

15   to conform to this internal aging clock.

16                 And the cells can go beyond that and the

17   human cells are now close to a hundred population

18   doublings, and in mouse and rat, over 150 population

19   doublings.

20                 If you look at the aging clock itself,

21   which are the telomeres, the telomeres are long and

22   they do not seem to shorten in culture, which goes

23   again with the idea that the cells do not senesce in

24   culture.
                                                                      101

1                   So     in         this      respect,    they      have

2    characteristics that are similar to what you would

3    find in embryonic stem cells, but also this internal

4    clock is actually not working.

5                   The phenotype of the cell is strange, and

6    it   doesn't   really      fit    anything    in   particular,   but

7    there is definitely no characteristics in these cells.

8                   These cells are blood hematopoietic stem

9    cells,   and   I    am not       going   to go     through   all the

10   details here, but if you do an extensive phenotype

11   characterization of the cells, they don't look like

12   blood.

13                  They      have       some     characteristics       of

14   embryonic stem cells, but there are a lot of other

15   ones that they do not have.              So they have some genes

16   that are turned on that are present also in embryonic

17   stem cells, which are the top two here, and then they

18   have on the cell surface antigens that you really only

19   find    on   embryonic     stem     cells,    or   primordial    germ

20   cells.

21                  So in some respects again these cells have

22   some features of embryonic stem cells, even though we

23   got these from the bone marrow of humans, mice, and

24   rats.
                                                                          102

1                  We then started trying to test initially

2    all in culture dishes what these cells could do, and

3    we asked whether they could differentiate in multiple

4    different cell types.

5                  And     because        our        initial     charge   was

6    actually to try to grow mesenchymal cells and make

7    bone and cartilage, that is what we did first.                    And so

8    what we showed in the culture dish is that if we

9    switch the culture conditions around, and actually use

10   ingredients    that       are     no         longer    supported     for

11   maintaining   the     stem      cells      in    an   undifferentiated

12   state, by actually switch them such that we hope that

13   we can turn on the genetic programs to make bone or

14   cartilage, and so forth, we could indeed do this.

15                 And     this      is      no      different     than   the

16   classical mesenchymal stems that have been described.

17   So we can induce the cells to become bone, and if we

18   say that they differentiated into bone tissue, it is

19   actually a calcified tissue at the bottom of a dish.

20                 We    can      induce        the     cells     to   become

21   cartilage that looks like articular cartilage, even

22   though it isn't very well organized.                       And you can

23   induce the cells to become lipid-laden lipocytes, and

24   we can induce them to become skeletal muscle cells.
                                                                  103

1                 And these cells can actually fuse and make

2    long muscle tubes almost, and we can induce the cells

3    to express a number of muscle markers for the heart,

4    even though we haven't really seen beating cells.

5                 And so we don't really know whether these

6    cells are heart muscle cells.          So this is still not

7    that strange, because there is this cell in the bone

8    marrow that has been identified that can do this.

9                 Now, we found three other lineages that

10   are completely outside of the mesenchymal lineage, and

11   some of this has been published, and most of it is

12   actually in press currently.

13                One of the things that we found is that

14   these cells can differentiate into cells that line

15   blood vessels, which we call endothelial cells.              And

16   we   have   been   able    to   show     that   these   cells

17   differentiate into cells that look like endothelial

18   cells, but also function as endothelial cells.

19                And   as   shown   in   this   picture   here     is

20   actually a blood vessel from an animal that had a

21   tumor underneath the skin, and we actually infused

22   human endothelial cells derived from human MAPCs in

23   this animal, and showed that these endothelial cells

24   seek out the tumor and actually help create new blood
                                                                        104

1    vessels in the tumor, which the tumor needs otherwise

2    it can't grow.

3                    And so this proves that these cells that

4    are in the bone marrow can differentiate into cells

5    that can make endothelium.            More surprisingly is that

6    the cells can differentiate into cells that look like

7    neutrons, look like astrocytes, and support themselves

8    in the brain, and to some extent function like these

9    cells in the brain.

10                   And    so     we      show     here        that    they

11   differentiated into cells that look like neurons and

12   have    electrophysiological               characteristics         like

13   neurons.

14                   And so this is the second major layer of

15   the embryo, and then we also have been able to show

16   that we can make these cells differentiate into cells

17   that look like liver cells, and actually function like

18   liver cells in a culture dish.

19                   And   so    this   would     mean   that    this   cell

20   population,       these       MAPC        cells,    can       actually

21   differentiate into all of the major components of a

22   human being, even though we only show a few cell

23   lineages here.

24                   I am not going to go through this in too

25   much   detail    because      it     is   highly    technical,     but
                                                                               105

1    essentially     we    have    not    been       able    to   use    genetic

2    marking to prove that this could all be derived from a

3    single cell, and we don't depend on population of

4    cells.

5                    So this fulfills two of the criteria of a

6    stem cell.      A single cell can differentiate and grow

7    for long periods of time, and can differentiate into

8    multiple different tissue cells.

9                    Two more sets of experiments were done to

10   try to gauge the potential of these cells.                       The first

11   one was done in an chimeric animal model, in which we

12   took the adult cells, and injected even a single adult

13   cell into the blastocyst of a mouse and asked what

14   would happen in this mouse, and whether we would see

15   contribution     to    some    tissues,          no    tissues,     or    all

16   tissues.

17                   So    we    injected        a    single      cell    or     we

18   injected   10    to    12    cells,    and       shown    here      are   two

19   animals.    The top one is obviously and the donor cells

20   here have a gene that if you stain it correctly the

21   cells turn blue.

22                   So what we did is we let the animals get

23   born, and we looked at the animals by genetic tools to

24   try   to   figure     out    if     there       were   donor     cells      in

25   multiple different organs.
                                                                           106

1                     And   we    also    then    took      the    mouse    and

2    actually cut a thin slice through the middle of the

3    animal and asked which organs would have blue cells

4    contributing to the mouse.

5                     The top mouse is an animal that if you

6    looked in the tail by genetic tools that we couldn't

7    find any donor cells, and the bottom mouse here, this

8    is its head, and over here would be his tail, and you

9    can see the spine, and the brain, and all the internal

10   organs.

11                    And you can see that the majority of all

12   the    tissues    of   this     animal     actually     appear    to    be

13   derived from a single blue adult cell that we have put

14   into the blastocyst.

15                    The efficiency isn't a hundred percent,

16   and this is shown on the bottom here, and so if you

17   look    over   here,     and    if   you    put   in    one    cell    per

18   blastocyst, 60 percent of the animals will not be

19   chimeric, but 30 percent or 40 percent of the animals

20   will be chimeric to varying degrees.

21                    If    you     increase     the   cell       number    the

22   chimericism goes up.           So this is probably not quite as

23   good as embryonic stem cells, but it is a fairly

24   significant degree of chimericism, and actually the

25   frequency appears to be one in three cells.
                                                              107

1                  So this would suggest that the cells can

2    probably make under the right circumstances more cell

3    types than we have be able to prove in a culture dish.

4                  We can also ask if we now take these stem

5    cells and give them to a mouse that is born, and we

6    give here again cells from the donors' mouse, which

7    again are blue, and we gave these to an animal that

8    was either not irradiated or irradiated with a small

9    amount of radiation therapy in the hope that maybe

10   that would help the cells engraft.

11                 We   used   an   immune-deficient    recipient

12   mouse, just because we were worried that the new genes

13   that are in the blue mouse might actually be a basis

14   for rejection.     So we don't know what would happen in

15   a non-immumodeficient mouse.

16                 If we do this, what we found is that we do

17   find engraftment in some tissues, but not all.           So,

18   for instance, in the top panel, we see that there is

19   engraftment    between    3    and   9   percent    in   the

20   hematopoietic system of this mouse, and we can find

21   the cells, and the blood we can find in the bone

22   marrow, and we can bind them in the spleen.

23                 And if we look in these animals, we can

24   also find over here, and what we did is we actually --

25   the blue color, we used an antibody that is now green,
                                                                     108

1    and co-labeled it with a red stain that stains the

2    specific tissue.

3                  And you can see in the liver that there is

4    areas in the liver where donor cells appear to be

5    present.      And there is areas in the guts, in the

6    villae of the gut, where donor cells appear to be

7    present.

8                  And there is areas in the lung where donor

9    cells appear to be present.             The presence of these

10   cells   can   be    seen   anywhere     from   four   weeks    after

11   transplantation, all the way to 24 weeks, which is

12   about six months, and the unfortunate thing with the

13   mouse model that we use is that these mice usually die

14   from    lymphomas    at    an   early    age    because   of    the

15   deficiency that they have.

16                 So we really have not been able to extend

17   the cultures or have the mouse experiments beyond 6

18   months, and so we are actually trying to go further.

19                 We transplant the cells in an animal that

20   is 6 to 8 weeks old, and so it is not a very young

21   mouse, and it is also not an old mouse.                   What we

22   showed is that if you damage certain tissues like the

23   hematopoietic system, and the gut system, that you

24   have increased engraftment, which is consistent with
                                                                          109

1    the fact that these cells go to places where the

2    repair might be needed.

3                     However,    we    did not     see    in    this   mouse

4    model engraftment in a number of other tissues, and

5    mind you that we gave these cells IV to an intact

6    mouse, which actually was not damaged in any way,

7    shape, or form.

8                     And we don't see engraftment in the heart,

9    skeletal muscle, or brain, and these tissues do not

10   proliferate.       We also don't see engraftment in the

11   skin and the kidney, and so these organs we didn't

12   really see very much engraftment.

13                    However, if you infused the cells directly

14   in the muscle, which causes damage, and actually done

15   the cells in response to the local cues within the

16   muscle, appear to be able to differentiate into muscle

17   cells.

18                    So it appears that these cells have the

19   ability    and    blastocyst       experiment    to    give    rise    to

20   many,    many    different     tissue    types,      if    given   post-

21   natally,    and    we   gave      them   as   stem    cells,   not     as

22   differentiated cells.

23                    They appear to be able to respond at least

24   in some respects to cues that are present in certain
                                                                            110

1    organs to differentiate into the cell type that is

2    specific for that organ.

3                   We have looked carefully at the cells in

4    culture and we do not see a significant number of

5    gross genetic abnormalities.                We have not looked with

6    a very fine-toothed comb through whether there might

7    be   some   minor     genetic     abnormalities        over    time    and

8    culture, and these studies are ongoing.

9                   If we infused the MAPCs in animals, we

10   really do not see any tumors, and so far we have not

11   seen that there are tumors that Dr. Gearhart talked

12   about, and we also have not seen any other tumors.

13                  Obviously if these cells come from bone

14   marrow     there    is   lots     of   precedent      on   bone    marrow

15   transplantations,         where    actually      if    you    do    this,

16   actually you do not cause tumors in patients.

17                  So MAPC that we have identified in our

18   laboratory seems to be a cell that is not senescing

19   and that can be found in adult tissues of humans, as

20   well as mouse and rats, and they seem to be capable of

21   giving rise to cells from the three germ layers, and

22   it   can    engraft      in   vitro    in    a   limited      number     of

23   tissues.

24                  Now, what I cannot tell is whether these

25   cells actually exist as such in a person, in a mouse,
                                                                       111

1    or in a rat, or whether our culture condition is

2    actually    such       that     it,     quote,       reprograms     or

3    dedifferentiates the cells that we take out of the

4    animal, and that then acquire this much more greater

5    potential, and I will come back to that in just one

6    second.

7                 So we now go back to my initial definition

8    of what is plasticity, which is really at the bottom

9    of all of the adult stem cell excitement.               I mentioned

10   initially that we would have to show that this is a

11   single cell of a rat, and I think the majority of

12   papers so far published have actually really not been

13   able to prove that a single cell could, for instance,

14   give rise to blood and muscle.

15                In vitro, we have evidence for that, and

16   in the blastocyst injection, we took a single cell and

17   actually found multiple different tissues.                  You could

18   ask, well, does it matter?

19                Does      it     matter    if   there    are     multiple

20   different cell types in the bone marrow, and I think

21   ultimately from an FDA or regulatory standpoint, it

22   will   matter,   and    we    will     have to   be    able    to say

23   exactly what cells that we are using to be able to

24   acquire a certain function in vitro, and so I think

25   that will be important.
                                                                     112

1                  The     second       question       is,     is     the

2    differentiation or is the remnant ES, and again you

3    could say, well, it probably doesn't matter.                   But I

4    think at this point in time, I don't think anybody in

5    this field knows whether these are left-over early

6    stem cells like ES cells, or whether these cells are

7    cells that can be reprogrammed, and redifferentiated,

8    and dedifferentiated under certain circumstances.

9                  Now, does it matter?         Well, you heard from

10   Dr. Gearhart that embryonic stem cells as such, and

11   not necessarily the differentiated progeny, but the ES

12   cells themselves can cause teratomas, and even though

13   nobody   in   the   adult   stem    cell   plasticity     era    has

14   actually   shown    teratomas,     it   doesn't    mean   that    it

15   might not happen.

16                 If it is dedifferentiation, it means that

17   you reprogram or you change the genetic material in a

18   cell.    But if you do that, currently we have no proof

19   that we actually change something and actually cause

20   an oncogene or something like that to be activated,

21   but that is definitely within the possibilities, and

22   that definitely needs to be looked at carefully.

23                 Is it fusion?        All the in vitro work that

24   has been published, including the data that I have
                                                                 113

1    shown to you today, I couldn't prove beyond any doubt

2    that that is not based on fusion.

3                 Our   in   vitro   data,   we   have   never   co-

4    cultured things with anything.          So we have single

5    cells that are deployed that can do multiple different

6    things, and so we can't really ascribe that to fusion.

7                 However, in vitro, I couldn't prove it to

8    you today, and we are doing studies to try to address

9    this.   I think that fusion might be the reason why

10   some studies in which a lot of pressure has been put

11   on to the system, which is essentially what those two

12   papers had to do in vitro.

13                So we have a lot of pressure exerted to

14   have that one cell survive after it fuses, and that is

15   a possibility.     Also, single cells that are found,

16   rather than whole colonies, may also be the result of

17   fusion, more so than experiments where you see huge

18   colonies arise in an in vivo model.

19                And so I think we currently cannot exclude

20   the possibility that some of the data is as a result

21   of fusion.   Some would say does it matter, and I think

22   it matters a whole lot, even though some investigators

23   say, well, if you fuse the cells and it functions

24   properly, it probably doesn't matter.
                                                                        114

1                    But I think ultimately that we do need to

2    make   sure     that   we   understand      the    whole    mechanism

3    underlying everything.            And is all this plasticity

4    clinically relevant?

5                    And so the majority of studies published

6    to date have actually shown the very low numbers of

7    tissue differentiated cells can be found in multiple

8    different tissues.

9                    A number of papers have been published,

10   two in particular.          The paper by Lagasse, et al.,

11   where they show that they could rescue an animal with

12   liver failure by bone marrow transplantation, but they

13   have significant degrees of engraftment.

14                   So that definitely was up to 80 or 90

15   percent of the liver could be replaced by bone marrow

16   cells.    And a paper by Don Orlic showing that if they

17   injected stem cells into the heart that was infarcted

18   that a significant amount of donor cells would be

19   found in the heart.

20                   And in the data that I have shown you,

21   that     we    have    up   to    5   to    9     percent    of    the

22   differentiated tissue that seems to be derived from

23   the graft.

24                   However,    the    majority       of   studies    again

25   haven't       really   addressed      the   other       question     in
                                                                             115

1    plasticity,     meaning     is     it      in     vitro        functional

2    differentiation?

3                  And there is really only a single study

4    that has been able to show that, and it is again the

5    same study by Lagasse, et al., who showed that if you

6    did bone marrow transplantation in an animal that had

7    a failing liver, you could rescue the animal and take

8    it off the drugs that kept it alive.

9                  Some    studies      have    shown        that    there     is

10   functional improvement, although the mechanism for the

11   functional    improvement        isn't    completely          known,    and

12   that is to some extent similar to what you heard from

13   Dr. Gearhart.

14                 And so there is a number of studies who

15   have    injected    cells   in    adults    in     organs       and    have

16   shown, for instance, that there was improvement in the

17   neuronal function, and that there was improvement in

18   heart function, although there is no proof that the

19   cells, per se, were actually responsible for doing

20   this.

21                 And     the    question           will     be     is     this

22   acceptable from a clinical standpoint, and if you show

23   only    functional     improvement         without           knowing    the

24   mechanism     for     knowing      why      we         see     functional

25   improvement, and in the long term, again, that is not
                                                                116

1    a tenable situation, and we really have to dig into

2    this much further.

3                   So what can adult stem cells be used for?

4    Well, I think like embryonic stem cells, or primordial

5    germ cells as you heard from Dr. Gearhart, the cells

6    are    good   tools   to   study   five   basic   principles   in

7    biology.

8                   And we can study self-renewal, and we can

9    study differentiation and redifferentiation if that is

10   indeed the case, and learn what the implications for

11   that are.

12                  And actually try to understand how organs

13   are being created, and what the genetic programs are

14   that you need to turn on.          The cells, like other stem

15   cell populations, could be used for drug discovery,

16   for drug toxicity screening.

17                  Adult stem cells could be used as systemic

18   therapies, and currently systemic therapies are done

19   with adult stem cells.        Bone marrow transplantation is

20   done every day in many, many institutions around the

21   world, and so we can infuse these cells if we do not

22   think that they make       tumors.

23                  So since adult stem cells don't seem to

24   have   that   as   their   side    effect,   theoretically,    we

25   could genetically correct cells for patients who have
                                                                            117

1    deficiencies of certain enzymes.               And the disease, and

2    Hurler's disease would be one example, and a second

3    possibility   would    be,    for instance,           in    hemophilia,

4    where you need to have a cell that produces clotting

5    factors.

6                  Or other congenital diseases, like Alpha-

7    1-Antitrypsin    deficiency,        or    it   could       be   used   for

8    systemic cell therapy, which you would have to treat

9    in many, many different places in the human being.

10   For instance, muscular dystrophy.

11                 So if you had a stem cell that was able to

12   engraft in most muscles, and you could genetically

13   correct it, you could correct that disease in patients

14   with that disease.

15                 Systemic       cell        therapy      may       be     more

16   complicated     with   cells        that       have    the      inherent

17   capability of making teratomas just because you would

18   always run the risk that teratomas might show up.

19                 And then again if this field progresses

20   further, the same diseases that has been quoted for

21   embryonic stem cell therapies would also be on the

22   list here, and if indeed the cells can differentiate

23   into functional neuron cells, they could be used to

24   treat Parkinson's disease and many other ones.
                                                                  118

1                     And since the cells can appear to be able

2    to   differentiate into      functional     liver    cells, they

3    could be used either in vivo to replace the liver, but

4    also     would   be   very   useful    to   make    bioartificial

5    livers, for instance.

6                     We have shown, and others have shown, that

7    cells from bone marrow can contribute to new blood

8    vessels, and so this could be harnessed to create new

9    blood vessels in vivo, or actually the opposite; lower

10   these cells with anti-cancer agents, and actually use

11   them in a anti-angiogenesis approach for treatment of

12   cancer, and then many other diseases.

13                    Again, we are not anywhere close to being

14   able to do this in any way, shape, or form, and a lot

15   of basic research still needs to go on.

16   So the first point that was on my previous slide, we

17   really    need    to spend   a   lot   of time     in   trying to

18   understand what these cells are and aren't.

19                    And at the same time, start thinking about

20   how we might be able to scale these up under GMP

21   conditions that conform with regulatory agencies, and

22   we will have to ask the question, as with any other

23   stem cell population, whether we will use the cells as

24   stem cells, or as more mature cells that have been
                                                                          119

1    educated to some extent to become the final product

2    are totally mature cells.

3                     And then again perform large scale culture

4    systems or develop large scale culture systems.                      And

5    then the last question is whether we should use these

6    cells in an autologous setting or in an allogeneic

7    setting.

8                     Obviously adult stem cells for a number of

9    diseases    could    be     used    in    an     autologous      setting.

10   However,    if    they     were    to    be    capable    of    repairing

11   hearts, and you have a heart infarct today, we would

12   not have adult stem cells sitting around instead of

13   your own to treat you at that moment in time.

14                    So I think there are some issues, and Dr.

15   Gearhart also brought up the idea that with diabetes,

16   for instance, in Type-1, is an immune problem, and

17   again autologous transplantation may not be the way to

18   go.

19                    I think that for adult stem cells, the

20   initial trials may well be autologous, but that in the

21   long term, to make it more cost effective and more

22   available    to     many    patients          with   certain    frequent

23   diseases,   that     it    might    have       to    be   an   allogeneic

24   therapy, and then we are actually faced with the same

25   questions that investigators that work with ES cells,
                                                                          120

1    and primordial germ cells are faced with.                    I think I

2    will stop there.         Thank you.

3                     (Applause.)

4                     DR.    KASS:       Thank     you    very    much,   Dr.

5    Verfaillie, for a clear, lucid, orderly presentation,

6    and it is very helpful to us.               The floor is open for

7    questions, comments, discussion.              Elizabeth Blackburn,

8    please.

9                     PROFESSOR BLACKBURN:          Thank you.      Could I

10   just   ask   a    couple    of     quick    clarifications.          Dr.

11   Gearhart     mentioned      in     response    to     Bill    Hurlbut's

12   question the difference between fetally derived human

13   cells and mouse embryonic stem cells with respect to

14   their teratoma producing properties.

15                    And I could not quite gather whether it is

16   human embryonic stem cells that are also known to have

17   any teratoma producing properties.                  Could you clarify

18   that for me, because you also had mentioned this, and

19   I wasn't sure if you were referring to the mouse

20   embryonic stem cell work or the human.

21                    DR. VERFAILLIE:       If you use either mouse

22   or     human           embryonic       stem         cells       without

23   predifferentiating them into a committed progenitor

24   cell, and you use the stem cells as such, they will

25   form teratomas, because it is one of the tools that
                                                                           121

1    investigators use that an embryonic stem cell has that

2    capability.     So they will form teratomas.

3                   PROFESSOR        BLACKBURN:         And    then       post-

4    differentiation?

5                   DR. VERFAILLIE:             I think there is very

6    little data on the human embryonic stem cells, post-

7    differentiation in vivo, and whether there is still

8    the tendency for these cells to make teratomas.

9                   PROFESSOR        BLACKBURN:         And    the      second

10   question, since I promised that I would ask you about,

11   is the fusion issue, and which of course you have

12   raised in your talk as well, but again a question of

13   clarification       for   me,    and   maybe   expanding        on    your

14   point that you said, well, fusions are going to be

15   problematic.

16                  I     mean,      the    thing      that     immediately

17   occurred to me was that these fusions, as reported

18   from     the   in   vitro       culture,    and    I     believe      from

19   engraftment into mice, that they showed aneuploidy,

20   which of course anybody being a hallmark of tumor

21   cells.

22                  So I wondered if those issues and perhaps

23   others were things you could tell us a bit more about

24   when you mentioned that you had concerns about the

25   fusions.
                                                                                          122

1                      DR.    VERFAILLIE:              Well,       I    think        it     is

2    something     that       because        of    the     papers             that    were

3    published that elegantly showed that if you took a

4    somatic     cell,       an   adult     hematopoietic              stem     cell        or

5    brain stem cell, and co-cultured it with embryonic

6    stem cells, and then put quite a bit of selectable

7    pressure     on    the       system    in    the    culture          dish,       they

8    proved that an embryonic stem cell quality could be

9    transferred to the blood brain stem cell.

10                     And    initially       they      interpreted             this        as

11   being reprogramming of the cell.                     But then it turned

12   out that there were four sets of chromosomes, and that

13   the cells fused.

14                     And they took these fused cells and gave

15   them   to    --     injected          them    into        a       blastocyst           as

16   hyperdiploid as cells with four sets of chromosomes.

17   One group was not able to create chimeric animals, and

18   the second group, under the direction of Dr. Austin

19   Smith, were able to create chimeras in the mice that

20   were what he calls unbalanced, meaning that he saw a

21   contribution        to       tissues,       and    that           four    sets         of

22   chromosomes are actually tolerated.

23                     For instance, the liver, where at least 50

24   percent of the cells, actually half, have two nuclei.

25   So I think that currently no investigator who has
                                                              123

1    worked with adult stem cells has set up the right

2    experiment to actually be able to disprove that it

3    isn't fusion.

4                I would argue that the data that I showed

5    today in vitro, where single cells make three layers

6    of the embryo, and these were euploid cells, meaning

7    that they had a normal set of chromosomes, and which

8    done in human, mouse, and rat, at the single cell

9    level, we can make      the three major layers of the

10   embryo.

11               So that would go against the argument that

12   at least in vitro, that all of it is caused by fusion.

13   In vivo, in our blastocyst experiments, 1 in 3 cells

14   could do it, which is much higher than the one in a

15   million cells that were quoted in the two papers that

16   were in Nature, but which indicated that one bone

17   marrow cell out of a million could actually make a

18   fused cell population.

19               And   I   think   one in   50,000   neural   stem

20   cells could actually cause fusion.      So that was a very

21   rare event; whereas, our events are higher.       We are in

22   the process of actually going back to these animals --

23   that we have cryopreserved, to try to identify that

24   since some of the transplants were done female into

25   male, we should be able to prove that we do not find
                                                                    124

1    the y chromosome in the engrafted areas and in the

2    chimeric   areas,     which    would    get    at   the   question

3    whether it is caused by fusion.

4                  And so I think we really need to set up

5    experiments   where    we     have   generic   markers    on   both

6    sides, meaning the donor and the recipient, so that we

7    can prove beyond any doubt that the in vivo results

8    would be the results from a fusion.

9                  PROFESSOR       BLACKBURN:       Yes,   I   totally

10   agreement with that.        I think the in vitro, and I am

11   very impressed by the in vitro results, and as you

12   said, there are questions in vivo.

13                 I think in-part my question was addressing

14   this issue, and I was asking about the tumor forming

15   ability or otherwise, because it was not exactly 4N.

16   It was the median number of chromosomes was different

17   from simply 4N, suggesting that there was aneuploidy,

18   and for example, one might not find Y chromosomes, for

19   example, because those had been selectively lost.

20                 So one would probably have to do much more

21   extensive genome-wide analysis of both of those to be

22   sure that there wasn't some genetic contribution from

23   the recipient cells.

24                 But I certainly am very impressed as you

25   say with the in vitro results, and they seem quite
                                                               125

1    unequivocal, and I guess which is the question that

2    you are addressing, and we will find out as the in

3    vitro --

4                DR. VERFAILLIE:      Yes, and I think we need

5    to set up the experiments where we have on multiple

6    chromosomes genetic markers.         You know, sequences that

7    we can distinguish the donor and recipient between.

8    So these experiments need to be repeated.

9                DR.     KASS:     Questions?       Janet   Rowley,

10   please.

11               DR. ROWLEY:       Well, I would like to ask a

12   question that will include both Elizabeth, as well as

13   Catherine, because I was struck in the data that you

14   presented on your human cell lines that you had passed

15   for more than a hundred generations, that telomerase

16   was still active.

17               And I just am curious about that, because

18   many of us do believe that that is, if you will, the

19   internal clock that limits the number of doublings

20   that those particular cells can undergo.

21               And     you     derive     these   from    adults,

22   presumably young adults in human, but at least adults,

23   and I am curious as to what you thought about the

24   mechanism of preserving the telomerase activity, and

25   maybe if Liz would have any further comments on that,
                                                                             126

1    because     again     one    of     the    critical       features      and

2    potential limitations of adult stem cells is the fact

3    that they would have potentially fewer doublings than

4    would those derived from embryos.

5                     DR. KASS:        Could I ask as a favor to the

6    non-scientists in the group if someone would just give

7    an ABCs on the telomerase matter, and just very, very

8    briefly, so that everybody can understand what the

9    discussion is about.          Elizabeth, or Dr. Verfaillie, if

10   you could just give the barest --

11                    PROFESSOR     BLACKBURN:           I     am    the    worst

12   person, because I will fall into expert jargonese and

13   so I will try not to.          So, telomerase keeps the DNA at

14   the     ends     of   chromosomes         replenished,          and    such

15   replenishment is necessary, because each time one of

16   our     cells    divides,     the    DNA      at    the    end    of     the

17   chromosome is a little bit whittled away.

18                    So, telomerase keeps putting back a little

19   extra DNA on to the ends of the chromosomes each time

20   on    average    a    cell    divides.         So    the       issue   that

21   Catherine pointed out in her talk was that if you

22   don't     have    telomerase        after      a    number       of     cell

23   multiplications,       that       whittling    away       process      would

24   have gone too far, and that sends a signal to cells to

25   cease dividing.
                                                                          127

1                   And so many, many normal cells in culture

2    are    characterized     by    the       inability      to    keep     on

3    multiplying.     Did that clarify the question?                So many

4    cells do not keep multiplying because they turn the

5    cells’   telomerase      off   as     part      of    their    natural

6    differentiated state.

7                   Cancer    cells,     on    the    other    hand,      have

8    telomerase, almost in a great majority of the cases,

9    and very up-regulated, and cells of the hematopoietic

10   system -- and I will defer to Catherine on this --

11   have an interesting intermediate situation, where they

12   have regulated telomerase activity that is turned on

13   in a natural and regulated way as the cells multiply

14   in response to signals in the body.                  Is that fair to

15   say?

16                  DR. ROWLEY:     Yes.

17                  PROFESSOR BLACKBURN:             So I think it is a

18   very interesting question of why telomerases is turned

19   on in those cells that are multiplying so well in

20   culture, and has there been a selective event that has

21   allowed those cells, that for some reason have turned

22   their telomerases on in the culture conditions.

23                  But   those     are        the    cells       that    are

24   outgrowing     perhaps    others     in    the       population,     and

25   perhaps that question might be answered by what is the
                                                                          128

1    clonal    efficiency       with     which    you    get    these    lines

2    growing out.       You may already know this.

3                     DR. ROWLEY:        But can I intervene, because

4    you assured that it was often turned on, and maybe

5    these cells are identified because they never turned

6    telomerases off.

7                     PROFESSOR BLACKBURN:              Yes, and I don't

8    know if that is the typical situation when one puts

9    cells into culture, and I thought that they more often

10   would     turn    off    and   an    earlier      subset    would    keep

11   multiplying, and again I want you to correct me on

12   that cell growth phenomenon.

13                    DR. KASS:     Thank you.

14                    DR. VERFAILLIE:          So currently we do not

15   know whether it is often turned back on in culture.

16   If   we    look     at   the    cultures,      for    the    first     40

17   population        doublings,        the   cells     appear    to     grow

18   slightly faster.

19                    And then a second wave of cells grows out

20   and it grows slightly slower.               So initially we thought

21   that maybe the more classical senescing cells were

22   disappearing, and that those were the cells that were

23   growing faster, and the you then select for the cell

24   that has inherent -- you know, has the system turned

25   on to not be subject to the clock of aging.
                                                                     129

1                 The frequency with which we can grow out

2    the cells from human bone marrow is we believe one in

3    a million bone marrow cells.           So it is a very rare

4    event, and so it will be quite difficult to actually

5    specifically ask whether it is turned on and then back

6    off, or turned off and then back on, unless we can

7    actually do some genetic trapping experiments to try

8    to ask the question.

9                 PROFESSOR    BLACKBURN:         I'm    thinking      of

10   David Beaches' experiments in which he was able to

11   show that cells would spontaneously, if you keep them

12   in culture, turn their telomerases back on, because

13   that gives them some selective advantage.

14                DR. VERFAILLIE:        Right.

15                PROFESSOR     BLACKBURN:        And      so   I    was

16   wondering if such selected advantages occur in your

17   situation?

18                DR. VERFAILLIE:        It could well be, and so

19   the culture conditions are very particular, and so I

20   didn't go into too much detail.

21                But   if    you   do    anything      wrong   to   the

22   culture conditions, we cannot create the cell lines,

23   and so it might well be that it is what we call in my

24   lab a cultural artifact what we see, which would mean

25   that these cells may not exist really as such, but
                                                                      130

1    actually      are   induced     to     become     this    long-term

2    proliferating cell by the culture conditions that we

3    put them under.

4                   PROFESSOR BLACKBURN:         Thank you.

5                   DR. KASS:      Janet, again, please.

6                   DR. ROWLEY:       I have two more questions.

7    One is a follow-up of a question that I asked you

8    about a year-and-a-half ago, on whether out of your

9    MAPC cells you can get hematopoietic tissue.

10                  DR. VERFAILLIE:         Well, I think I showed

11   you in vivo that if you infuse the cells into mice

12   that   were   either   not     irradiated    or   sub-irradiated,

13   that the cells appear to be able to differentiate into

14   hematopoietic       elements    that    have      red    cell,   and

15   granulocytic markers.

16                  In vitro, we have had more difficulty to

17   try to do that, even though it appears now that we can

18   at least get for people who don't understand this, but

19   what would be yolk sac hematopoiesis, even though we

20   haven't really seen hematopoiesis that would occur in

21   the embryo proper.

22                  But we can find cells that look like the

23   cells that have been created at the earlier stages of

24   development, where the initial one is made, which is

25   in the yolk sac.
                                                                                131

1                       DR. ROWLEY:        And the other question is

2    more    a     more    practical       question.              I   don't    know

3    precisely how many cells would be required to treat an

4    adult patient with a particular disease, and are the

5    number of cells required, or what kind of limitations,

6    using your system, would be faced if you have not one

7    patient, but hundreds or thousands of patients that

8    could benefit from a particular therapy?

9                       Is this really going to be an applicable

10   strategy?

11                      DR. VERFAILLIE:          I think it is a bit too

12   early    currently         to   really     be     able      to   answer   that

13   question.      We have been able to take cell populations

14   and    have    them       undergo    80    to     a    hundred    population

15   doublings, which is really if you were able to do that

16   and not throw cells away along the way, it is 10 to

17   the 50th cells or something like that.

18                      So it is an enormous number of cells that

19   you can in theory create.                  What I didn't go into too

20   much detail on is that the way that we have to grow

21   these   cells        is   under     very    low       density    conditions,

22   meaning that the cells have to be far away from one

23   another,      or     otherwise      they     do       not   maintain      their

24   undifferentiated state.
                                                                    132

1                    Which is quite different from embryonic

2    stem cells, which tend to grow in tight clusters.

3    From a bioengineering standpoint, meaning scaling it

4    up to making hundreds of millions of cells, will be a

5    major bioengineering question of how we can actually

6    adjust the system to be able to do that.

7                    But on theoretical grounds, you know, if

8    you could overcome all the bioengineering problems,

9    you should be able to create enough cells to treat

10   multiple individuals, rather than a single individual

11   at a time.

12                   DR.   KASS:     Question.     Robert    and   then

13   Mike.

14                   PROFESSOR     GEORGE:     Just    a   very    quick

15   question of clarification in response to Janet's first

16   point.    On this question of whether they were                  --

17   whether   the    teleomerases     were   turned   off   and   then

18   turned back on in the culture.

19                   If it is not that, and if that's not what

20   is happening, the other possibility is that they were

21   never off to begin with?

22                   DR. VERFAILLIE:    Correct.

23                   DR. KASS:     Mike Gazzaniga.

24                   DR. GAZZANIGA:      Again, thank you for a

25   very excellent talk and a cautious talk I thought.                   I
                                                                 133

1    thought it would be helpful for us to understand the

2    new pressures of a biologist like yourself, which are

3    the following.

4                 Here      you      have    this    fantastically

5    interesting finding, and up until 5 or 10 years ago,

6    the normal way that such things would be treated is

7    you publish the work in peer review, and then you make

8    the stuff, whether it is reagents, or whether it is

9    cell lines available to others for reproducibility.

10                And that is a normal sequence of events

11   that we are all familiar with.          And now we have the

12   bio-med   inserting    itself    into   these   laboratories,

13   where all of a sudden it becomes proprietary goods

14   from this work.

15                When the original media picked up on your

16   story, and I guess it was The New Scientist, there was

17   this cryptic little paragraph in there about how they

18   had seen the patent on some of this work, which is a

19   very complete description, and how does that -- what

20   is going on here?

21                How can -- and this is where I would like

22   to   go   obviously,   and   obviously    it    is   good   for

23   everybody here to get these cell lines that you have

24   out to other labs, and reproducibility, and then the

25   process goes forward.
                                                                        134

1                    Are you constrained in some way, and has

2    life been made complicated because you didn't have

3    full public funding and you had to use this other

4    money, or was that your own?          What is going on?

5                    DR. VERFAILLIE:        So the work was really

6    done at the university with NIH funds and university

7    funds,    and   so    there   was    really   no     private     funds,

8    except for the small amount from the company that was

9    listed in the beginning, has gone into the work that

10   we have done.

11                   And because of the possible importance of

12   the observation, the university, as well as myself,

13   thought we should get some kind of protection, even

14   though I am not sure that you can truly patent stem

15   cells, because all of us have them.

16                   But   just    such   that     we    would   be    in     a

17   position to work with biotech companies to be able to

18   produce large-scale numbers of cells and things like

19   that, which is hard to be funded to known private

20   funds.

21                   So there is patents pending on the cell

22   population.      Currently, that really has not precluded

23   us   of   collaborating       with    other        institutions,       or

24   investigators within the same institution.
                                                                      135

1                    So they have collaborations with 10 or 15

2    different groups within the U.S., or outside of the

3    U.S., depending upon the expertise that we need, to

4    try to recreate the cells in other laboratories, and

5    actually       use    their     expertise,       since     I    am     a

6    hematologist, and not a liver physician or a neuro

7    scientist.

8                    And to actually be able to use expertise

9    in other people's laboratories to move the research

10   forward.       So there are some minimal ties attached to

11   working    with       the    cells,   but    I    think    it   isn't

12   overcomeable, and it really has not been an issue with

13   other academic investigators to collaborate with them.

14                   And teaching people from those labs to

15   come and to grow the cells, and at least start working

16   with the cells.         But it is a very complicated and it

17   is a -- and I have had myself a lot of problems in

18   trying    to   find    the    right   patent     between   potential

19   biotech interests and academic interests.

20                   DR. GAZZANIGA:         Right, and you are not

21   alone in that dilemma.          So are there other MPAC lines

22   at other institutions now that behave like yours, or

23   is yours still the Golden Grail here?

24                   DR. VERFAILLIE:         We have given out the

25   mouse, and to some extent, human MAPC lines to other
                                                                 136

1    investigators who are now setting the lines back up.

2    We are also explaining and teaching people how to

3    create them from beginning bone marrow.

4                  And I know that there is one group in

5    Japan who I think pretty much as the system set back

6    up from human bone marrow.        You know, they still need

7    to do some additional studies to prove that it is

8    really MAPCs, but we trained a person from there for 3

9    or 4 months in my lab, and they went back to Japan,

10   and were able to it appears to recreate them.

11                 DR. KASS:    Could I ask a couple of sort of

12   semi-scientific    and    semi-practical       questions?   How

13   hard is it -- I mean, you have just indicated that not

14   many people have already been able to do this, but how

15   hard is it to find these cells?

16                 And by which I mean two pieces, and in how

17   many individuals in which you look for them can you

18   find them?    And how hard is it to find -- how rare are

19   they, and how hard is it to find in any particular

20   individual?

21                 Both of these questions bear upon at least

22   a preliminary assessment of how useful this might be

23   clinically    speaking    down   the   road,    although things

24   could change where you might be able to enhance the

25   yield.
                                                                      137

1                  But could you give us a preliminary sense

2    of this?

3                  DR. VERFAILLIE:        I think we have studied

4    now between 70 and 80 normal humans to try to identify

5    the cells.    The age range, the youngest donor was two,

6    and the oldest donor was 55.             The majority are young

7    adults who want some money to donate bone marrow at

8    the universities.

9                  DR. KASS:      The two-year old?

10                 DR. VERFAILLIE:        No, the 20 year olds.

11   The 2 year old actually did a bone marrow donation for

12   a sibling who needed a bone marrow transplantation.

13   So we have been able to create the cells I would say

14   in about 70 percent of the individuals that we have

15   looked at.

16                 Whether   that     means     that   the    other     30

17   percent didn't have it, or there was some technical

18   issue that came about, and we were not able to create

19   them, we start out with 10 milliliters of bone marrow,

20   and   we   would   usually    find   a    few   clones   that    can

21   actually grow out.

22                 And so really the frequency is quite low,

23   and it is one in a million, and that is at least the

24   estimate that we have right now.           But there is lots of
                                                                             138

1    bone    marrow     and    so    one     in    a     million     isn't     an

2    impossible task to do it.

3                     DR. KASS:       And could I also follow up on

4    the    question     of    these       cells       and   their    promise,

5    assuming   the     best,       and    the    embryonic       stem   cells,

6    assuming their best.

7                     This    is    not   a question         of   whether    one

8    should prefer one line of research or another, or

9    whether we should now go ahead with them.                           But is

10   there anything specific that you could imagine could

11   not be done therapeutically with these MAPC cells that

12   you    would   then      need   cells       derived     from    embryonic

13   tissue to do?

14                    Or is this in the rosiest division, is

15   this really a substitute, and one that might even have

16   the rejection problem solved if I am dreaming?

17   And this is not a question about whether the other

18   research should go forward, but really what is the

19   best promise of this research so that at least we can

20   think about it?

21                    DR. VERFAILLIE:            Well, I think that the

22   data that we have in vitro suggests that we can create

23   cells of the three germ layers of the embryo, and so

24   theoretically, you could envision that you might be

25   able to make more than we have done so far.
                                                                 139

1                   We have made liver-like cells, and brain-

2    like cells, and epithelial cells, and we have not

3    tried all the other ones.          In vivo, the blastocyst

4    experiment, unless that is a fusion event, and if it

5    isn't a fusion event, would indicate that the cells

6    hold the inherent promise of making all the different

7    cell   types   that   make   up   the   tissues,   the   somatic

8    tissues of an animal.

9                   So again that would suggest that is under

10   -- that if we changed culture conditions further that

11   we might be able to, for instance, create insulin-

12   producing beta cells, which we haven't done, or create

13   two heart muscle cells that function like heart muscle

14   cells, and don't just look like it.

15                  So if all these promises hold true, and if

16   we continue the cultures and they can be expanded even

17   further into 80 or 90 population doublings, and so

18   there are lots of ifs here, they may be able to be

19   used to treat a large number of diseases.

20                  The problem at this point in time is that

21   there is so many ifs that it is a very difficult

22   question to specifically answer.

23                  DR. KASS:     Of course, and I appreciate

24   that, and on the question of the longlivedness, or the
                                                              140

1    half-life of these things, you have gone through -- in

2    vitro is what?     It is what?

3                 DR. VERFAILLIE:      From 80 to 100 population

4    doublings.

5                 DR. KASS:     And it is obviously too early

6    to say how much longer, and whether those conditions

7    are matched in vivo.     But when the people say that the

8    promise in terms of longevity for cells derived from

9    the adults is really much less, is there anything to

10   be said on that question of the basis of knowledge now

11   had?

12                DR.    VERFAILLIE:      Human   embryonic   stem

13   cells have been kept in culture now for 350 or 400

14   population doublings.     So that is 3 or 4 times as long

15   as the adult cells.      So we are striving to go there,

16   but we just need time to do that.

17                Are these cells going to be able to do

18   that?   As far as we can tell, after 80 population

19   doublings, there is no shortening of telomeres, and so

20   that means that there is at least another 50 or 60

21   left.

22                If for some reason telomerase is shut off

23   along the way for reasons that we currently don't know

24   why that might be, then the longevity would be less

25   than what has been shown for embryonic stem cells.
                                                                   141

1                   Now, for classical adult stem cells, if

2    you take hematopoietic stem cells that make blood, but

3    not   something    else,     they   would   not   go    for     80

4    population doublings.

5                   So there is something special about these

6    cells, that they can overcome this senescent block at

7    60 or 70 population doublings, which is actually long

8    for any other adult stem cell.

9                   DR. KASS:   Thank you very much.        Questions

10   or comments?    Janet again, please.

11                  DR. ROWLEY:     Coming back again to partly

12   the real world in this iffy situation, and it is a

13   question   of     the   practicality    for   treatment       for

14   particular individuals.

15                  It seems to me that the notion that you

16   might be able to derive these MAPC cells from an

17   individual who had some medical problem might have

18   some limitations because it probably takes 3 to 6

19   months, or so to get enough cells to then be able to

20   use them therapeutically in that individual, and that

21   is always assuming that the individual has some kind

22   of a somatic disease, and not the basic underlying

23   genetic problem.

24                  So then the way to get around that if it

25   really is 3 to 6 months, and you don't have that
                                                                       142

1    window of time, would be to do somatic cell nuclear

2    transplant.      Now, have you ever tried that in your

3    MAPC cells?

4                    DR. VERFAILLIE:       In collaboration with Dr.

5    Jaenisch, and two weeks from now we will try the mouse

6    MAPC    cells    in   mouse    eggs,    and    ask     whether    the

7    efficiency of nuclear transfer would be closer to what

8    you would see with embryonic stem cells, and where the

9    efficiency is much, much, much higher than if you use

10   a classical adult cell.

11                   And   that    might    improve       efficiency     of

12   making cloned embryonic stem cells.

13                   DR. ROWLEY:         But I am thinking of the

14   other     experiment.         You   have   a    patient    who      is

15   desperately ill, and so you would have cells from that

16   patient, and you would want to use the nucleus of the

17   patient's cells into your MAPC cells, and so that is a

18   different thing.

19                   You have got these cell lines, and how can

20   you make them more compatible with the patient, and

21   agreeing that you can't get rid of the mitochondrial

22   problem    unless you    do     additional     manipulations and

23   strategies.
                                                                            143

1                    But have you ever tried to replace the

2    nucleus in your MAPC cell with a nucleus from an adult

3    somatic cell?

4                    DR. VERFAILLIE:       No, we have not yet.

5                    DR. ROWLEY:     Do you plan to?

6                    DR. VERFAILLIE:       We might.

7                    DR. KASS:     We could always get everyone at

8    the age of 15 to put away a little bit of marrow for

9    the time that we might need it.

10                   DR. ROWLEY:      Another reason to save cord

11   blood.

12                   DR. KASS:       This is your chance, council

13   members.   This is a wonderful opportunity.                   Questions?

14                   DR.   ROWLEY:         Well,    I    would       just     be

15   interested   from     Catherine's      point       of    view    on    her

16   answers to some of the questions, to the two questions

17   that I posed at the end to John Gearhart, and again

18   give her the option to do this as a written response

19   rather than a direct response, but I think it may be

20   easier to -- and the second question, which may be

21   very   simple    to   answer     in   terms    of       the    kinds     of

22   restrictions that you find now in funding.

23                   And I would assume since you are dealing

24   with adult cells that there aren't any, but I would be
                                                                            144

1    interested in your perspective on the funding, in both

2    government and other agencies.

3                      DR. VERFAILLIE:           Well, currently for the

4    work that is ongoing in my group, which works with

5    adult stem cells, actually the amount of funding that

6    has become available through the NIH has increased

7    dramatically over the last few years to support this

8    kind of research.

9                      So that has not been a problem.                I have

10   wanted to compare these cells carefully with embryonic

11   stem cells, and so we are in a position currently to

12   do this in a mouse, but mice aren't humans.

13                     And so we have really not been able to do

14   that until earlier this year when human embryonic stem

15   cell   research      was   allowed      in academic       institutions

16   under NIH funding.

17                     And as I mentioned, we had actually gone

18   out and tried to recruit an investigator with that

19   kind   of    expertise     to    be    in    a position     to   try     to

20   address some of the questions that have come up here,

21   and are these cells going to be equipotent.

22                     And I think to date, even though they are

23   exciting and they seem to be quite potent, I can't

24   really      say    whether      that   is     the   case.        And     so

25   ultimately we won't be able to answer this question
                                                                                145

1    until we can truly compare them and not across country

2    borders,        but actually within           the    same     institution,

3    where people can look at the two cell populations at

4    the same time.

5                      And so in that respect, I think that the

6    lack of funding for embryonic stem cell research in

7    humans has made it impossible up until just recently

8    to be able to do that.

9                      DR. KASS:      Michael Sandel.

10                     PROFESSOR SANDEL:          I wonder if I could put

11   to   you    the       same    question   I    put     to      the    previous

12   speaker.        Given that some people regard embryonic stem

13   cell research as morally problematic, what would you

14   think      of    the    idea    of     imposing      a     moratorium        on

15   embryonic stem cell research until we could assess

16   what might be achieved by adult stem cell research?

17                     DR. VERFAILLIE:        I think that my answer is

18   very    much     in     line   with    what    you       heard      from   Dr.

19   Gearhart.        I think that the main reason why we -- to

20   investigate in the field of embryonic stem cell --

21   human embryonic stem cell research is to be able to

22   compare and contrast the two cell populations at the

23   same time.

24                     I    also    think   that    what      we    did    in   our

25   culture dishes to try to differentiate these MAPCs
                                                                 146

1    into liver-like cells or neuronal-like cells is really

2    based on what has been learned from mainly the mouse

3    embryonic stem cell field, where investigators have

4    been able to take these cells and drive them in vitro

5    to become certain cell types, even though that is not

6    a hundred percent fool-proof, and it is not completely

7    figured out how you should do that.

8                So   I   think   if   you   have   a   number     of

9    different cell populations at the same time, we try to

10   test all these different questions.        What we learned

11   in adult cells might be applicable to embryonic stem

12   cells if they are the cells that ultimately will be

13   the suitable source for our clinical applications or

14   the other way around.

15               And so I think stopping research in one

16   field actually will slow down research in the other

17   field, and it would be either way.      In other words, if

18   you stop our research in adult cells, or embryonic

19   stems, as I think what can be learned in the two

20   systems should be translatable in the other system.

21               And so I think if you were to ban all

22   embryonic stem cell research, it would really slow

23   down the insight that could be gained in adult stem

24   cell research.

25               DR. KASS:   Rebecca Dresser.
                                                              147

1                PROFESSOR DRESSER:         This is unfair, but I

2    am wondering if you      had any ideas about the cost of

3    such a procedure?    I mean, just based on what you have

4    done in mice, and you mentioned at the very end that

5    to be cost effective that you would probably would

6    have to just have a number of cell lines and not rely

7    on the patient cell.

8                Is this going to be a very, very expensive

9    technology, and where we have to worry about -- well,

10   if all these ifs work out, will we have to worry about

11   who has access, or will it be comparable to the stem

12   cell transplants that we do now with bone marrow now?

13   Or what do you think?

14               DR. VERFAILLIE:      Well, I think it will be

15   relatively expensive if you do it on a single person

16   basis, and you will have to create the cell lines from

17   the beginning, rather than go going to a frozen stock

18   of cells, where you have a very well-qualified product

19   to start with and where you expand cells.

20               And     so   you   might    even   have   already

21   committed cells frozen as well, and so the cost to get

22   to that point would have to be incurred once rather

23   than doing this over, and over, and over again.

24               The costs I think -- well, it is hard to

25   say, because I am not sure how much of the regulatory
                                                                148

1    issues we have actually complied by at this point in

2    time to actually truly gauge how much it would cost.

3                 But I think that by the time that you do

4    all the quality control tests for infectious agents

5    and things like that, that amounts to quite a bit of

6    money for each cell line that you try to establish.

7                 And in the long term I think it would

8    probably be more cost effective if you would have a

9    therapy for heart infarcts that you could go to a

10   limited number of cell lines.        And to put numbers of

11   them, I don't really know.

12                It would probably be in the range of a

13   bone marrow transplantation currently, which is quite

14   expensive.    So it is anywhere between $50,000 and

15   $200,000 per patient.

16                If   you    had   qualified   cells   that   were

17   frozen, and then you could expand them for a short

18   period of time and do a limited number of tests at the

19   end, the amount of cost incurred would really be all

20   up-front, and then there would be a relatively small

21   amount per patient.

22                PROFESSOR    DRESSER:     I   guess   the    other

23   thing is that bone marrow transplants work fairly well

24   with some illnesses and not with others, and would you
                                                                            149

1    expect to see those kinds of results with these kinds

2    of therapies?

3                    DR. VERFAILLIE:          I think that would highly

4    depend on the type of disease that you tried to treat.

5    You know, you are all well aware of the treatments

6    that have been used for Parkinson's disease, which the

7    trials   that    were       done   in    Sweden     have   made      little

8    complications.

9                    But when this was extended in multiple

10   hospitals   in        the    West,      there     were     a   lot     more

11   complications if it was done on a larger scale.                       So I

12   think that depending on the disease that you go after

13   that it may work better or worse, and it is really way

14   to early to be able to comment on that.

15                   DR. KASS:      Bill, do you have a question?

16                   DR. HURLBUT:            Well, if we have time, I

17   would like to ask a couple of scientific questions if

18   that is all right.

19                   DR. KASS:      Please.

20                   DR.     HURLBUT:          Do    I    understand        this

21   correctly that you are saying that your MAPC is put

22   into the blastocyst to perform more cell lines than do

23   other adult stem cells?

24                   I thought that adult stem cells generally

25   formed lines in a blastocyst?
                                                                              150

1                     DR. VERFAILLIE:            There are 3 or 4 papers

2    published       on     adult     stem       cells      into    blastocyst

3    experiments.         There is one paper published by a German

4    group, where they             took    purified      hematopoietic stem

5    cells, and injected them into the blastocyst, and what

6    they were able to show was that the cells gave rise to

7    some hematopoietic elements, and that they actually

8    recapitulated           the      developmental           behavior          of

9    hemoglobins,         which    switched      at different       stages of

10   development during embryos, fetuses, and then adults.

11                    They did not see any contribution outside

12   of the hematopoietic system.                   The second paper is a

13   paper    from    a     Swedish    group,       where    they   had   taken

14   neural    stem       cells     that     have     been    cultured,       and

15   introduced them in the blastocyst, and as far as I

16   know, they have never had animals been born alive.

17                    And    they     saw    a   contribution       to    a   few

18   tissues, but not all tissues of the mouse fetus.                         And

19   in the last papers, we did a paper by Austin Smith,

20   the one that reported on fusion, where they had taken

21   defused cells and given them to a blastocyst again,

22   and it showed a contribution in one animal that was

23   born, and that was really only a single animal, to the

24   liver and a few other tissues.
                                                                   151

1                 But   it    was   not     quite   the   amount     of

2    contribution that I showed in the picture here, where

3    every single tissue of the mouse appeared to be having

4    a fraction of the single MAPC cell.

5                 DR. HURLBUT:      That is very, very exciting.

6    Another question that I think might be of good general

7    interest to our council, but he question of whether

8    transdifferentiation is occurring, or even the process

9    of embryonic stem cells just differentiating, it is

10   always clouded by the question of how do you know when

11   there is actual differentiation taking place?

12                In other words, just because you follow

13   one or two gene expressions, you don't know, and one

14   of the problems with embryonic stem cell therapies

15   will be to get the target tissues up to speed, like

16   beta cells producing enough insulin.

17                I know that there are advances being made

18   on   this,   but   can   you    just    give    us   a   general

19   description of how you identify when you are satisfied

20   that a tissue has in fact been produced?

21                And maybe tell us a little bit about the -

22   - maybe we need a little education on messenger RNA

23   assays.

24                DR. VERFAILLIE:         Okay.     The criteria to

25   say that you produced tissue I think needs to include
                                                                                 152

1    that     you   turned    on       the     genetic     program        that     is

2    compatible with the tissue that you want to produce.

3                     You    find       therefore     proteins        from        the

4    genetic    program      in       the   cells,   and     the    cells        have

5    morphological changes consistent with the cells that

6    you are looking for, and the cells have functional

7    characteristics of the tissue that you are looking

8    for.

9                     So what happens in a cell is that in an

10   undifferentiated state a number of gene programs are

11   shut down, meaning there is no transcription to the

12   messenger      RNA,    and       you   will   find    no    protein,        and

13   therefore no function.

14                    During a differentiation process, you come

15   in with a growth factor or a cytokine, or a stimulus

16   from the outside, and you trigger a certain set of

17   signals that then open up a new genetic program and

18   the first thing that happens is that you transcribe

19   messenger RNA, that then gets translated into proteins

20   and/or     sugars,      that       then     supposedly        give    a     new

21   function to the cell.

22                    So what we have been looking for in vitro,

23   and that is where most of our work has been done

24   initially, is actually taking an undifferentiated cell

25   and    showing    that       a    certain     genetic      program        isn't
                                                            153

1    turned on, meaning that you don't find mRNA, and you

2    don't find protein, and you don't find function.

3                 We then switch the culture conditions and

4    add triggers by trial and error, to a large extent to

5    try to activate certain genetic programs.         And if we

6    do that, we look for protein and mRNA first.

7                 So we look to prove that the genes are

8    turned on, and then we look to prove that these gene

9    products actually give rise to proteins.       We have gone

10   to the next step also and actually tried to then take

11   the cells that we believe that are like brain or like

12   liver, and started asking questions.

13                If it is a liver cell, it should secrete

14   certain   things.   It   should   have   the   machinery   to

15   detoxify blood and things like that.       So we have been

16   able to show that in the liver lineage, for instance,

17   that we do turn on the programs to make albumin, which

18   is one of the major proteins that is being secreted in

19   the liver and is present in the blood.

20                These cells have, for instance, cytochrome

21   p450, which is a massive machinery in the liver that

22   helps detoxify the blood components.       And we can show

23   that it is there, and it responds in the correct ways

24   as liver cells would do.
                                                                   154

1                   So that is what you do in vitro, and in

2    vivo, it is a bit more complicated, and you really

3    need to use animal models where there is a disease.

4    So you would have to show that the cells ingraft and

5    you can find the donor cells.

6                   You would have to show that they turn on

7    RNA    and   protein,   and   therefore    have   this   genetic

8    program turned on.        And then function, which means

9    that if you take an animal that has a failing liver,

10   and you give the liver cells to this animal, the

11   animal will now live without having drugs that keeps

12   it alive.

13                  And so that would prove that the cells

14   that you put in have actually acquired the ability to

15   function like a liver cell.          And so for adult stem

16   cell research, very little proof of the latter is

17   actually present.

18                  For embryonic stem cell research in mice,

19   there is a lot of evidence, and in the human embryonic

20   stem cells, that evidence is just starting to become

21   available, just like it is with adult stem cells.

22                  DR. HURLBUT:     Could I ask one last little

23   question?     How many genes are we talking about here;

24   like   hundreds,   or   thousands,   and    how   many   do   you

25   monitor in fact?
                                                                    155

1                     DR. VERFAILLIE:    Well, we usually monitor

2    between     --    well,   there    is   probably    hundreds     of

3    thousands that get turned on, and so using the new

4    technologies, the array technology, and the proteomics

5    technology, that is one of the things that we are

6    looking at, because it will give us a much better

7    insight in the whole programs that are being turned

8    on.

9                     We just pick and choose the ones that we

10   think are known to be important at certain stages of

11   the differentiation.        So, for instance, if you go from

12   a stem cell to a liver cell, we know that you have to

13   turn on X number of genes that happen to be known to

14   be turned on.

15                    So we look at 2 or 3 that are early, and 2

16   or 3 that are in the middle, and then 5 or 6 at the

17   end.      We have not exhaustively looked at all of them

18   yet.

19                    But I think with the human genome being

20   sequenced, we now have the tools in hand to now take

21   cells created from stem cells and look at the whole

22   program of genes that is present, and what we created

23   in    a   culture   dish,   compared    to   what   is   actually

24   present in real life in vivo, and get a feel of how

25   closely we actually are getting to the real cell.
                                                                            156

1                   DR. HURLBUT:        Thank you.

2                   DR. KASS:     Could I -- Robby, did you have

3    a question?     Why don't you go first, because I have a

4    couple of things as well.          Please.

5                   PROFESSOR GEORGE:         Actually, I just wanted

6    to follow up the question that Dr. Kass asked earlier

7    just for clarification, and I recognize that there is

8    a great deal of uncertainty as to what the future

9    holds   in    your    area   for    research,         as   well   as     in

10   embryonic stem cell research.

11                  And    estimating      or    evaluating       what      the

12   prospects     are     therapeutically            is    a   speculative

13   business, but having all of that in mind -- and I was

14   not   clear   in     responding     to     Dr.    Kass     whether     you

15   identified some areas in which knowing what we do know

16   now about the differences between embryonic stem cells

17   and the MAPC cells, it is possible to identify some

18   areas where we just know that whatever the prospects

19   are for MAPC cells that they won't be able to do, or

20   our therapies won't be able to be developed based on

21   them to do certain things.

22                  And that there is at least a prospect of

23   embryonic stem cells being used to do.

24                  DR. VERFAILLIE:        It is so very hard for me

25   to answer that question, just because embryonic stem
                                                                    157

1    cells have been worked with for so much longer, and so

2    investigators have been able to, for instance, make

3    cells that secrete insulin to some extent on demand,

4    which has not been accomplished with adult stem cells.

5                 There is a little bit of evidence from

6    pancreatic   tissue       itself   that       there    might     be

7    precursors   that   can   do   that,    but   from    MAPCs,   for

8    instance, we have not been able to do this yet.

9                 It doesn't mean that we can't.              I don't

10   know that answer.     So there is a lot more experience

11   with embryonic stem cells and there is a lot more --

12   at least in the mouse system, there is a lot more

13   known on how to try to trigger certain differentiation

14   programs and whether the MAPCs will respond to the

15   same extent and to the same degree.

16                And I think that currently I can't really

17   answer that question.

18                PROFESSOR GEORGE:         But asking if you look

19   at it and not asking what do we know MAPC cells will

20   be able to enable us to do, and have a prospect of

21   doing, that embryonic stem cells have a prospect of

22   doing.

23                But if we simply ask the question as do we

24   know just on the basis of the facts of what we know

25   about the differences, and that there are in fact some
                                                              158

1    things that MAPC cells, no matter what, won't be able

2    to do.   Or is the answer that we just don't know?

3                   DR. VERFAILLIE:      I think we don't know

4    currently, and I can't really answer that question,

5    because we just don't know at this point in time.

6                   DR. FOSTER:    I just want to interrupt with

7    this one point.        Those questions are really hard to

8    answer, but there is another whole area that is going

9    to impact what you are going to use cellular based

10   therapy for.

11                  And    that has   to do   with   good vectors,

12   retroviral gene therapy, and that you are going to

13   accomplish with other diseases that you don't have to

14   use cells for at all.

15                  I mean, the most recent thing in severe

16   combined immunodeficiencies in humans, is you put a

17   retrovirus in, and you put the common gamma chain in

18   for about five cytokines, you know, for these kids.

19   It was just in the New England Journal a couple of

20   weeks ago, or three weeks ago, or something like that.

21                  And they are now two years out, and so

22   there are going to be a whole lot of diseases that you

23   are not going to have to use regenerative therapy or

24   cell therapy.        You can't predict those things either

25   at this point.
                                                             159

1                 So I think if you try to jump way ahead of

2    what the basic science is doing, then you are prone to

3    error, and I know everybody wants to know whether an

4    adult cell is better than an embryonic stem cell, or

5    something like that.

6                 And I don't think you can answer those

7    questions, and one of the things that we have heard

8    from both the investigators this morning is that they

9    cross-fertilized with each other.

10                And so -- I mean, that you could not have

11   done what you are doing in the adult cells without

12   what had already been done with the embryonic cells.

13                So I just would argue against trying to

14   push investigators to say whether an adult stem cell

15   can do this or do that at this point, because we have

16   not   even   taken     into   consideration    many   other

17   approaches to human disease.

18                I don't mean to be fussy, but I do think

19   that that is an important thing.

20                PROFESSOR   GEORGE:    But   I   was   actually

21   asking -- well, I think the question I asked was that

22   it really is about what we know now.      The question is

23   do we know now that there are certain differences,

24   that as a result of which the prospects for the one
                                                         160

1    area are different from the prospects of the other.

2    And I got my answer.    Thank you.

3                DR. KASS:     Let me take the privilege of

4    the Chair to expand in a way Dan Foster's comment in a

5    direction that he might not have intended.

6                DR. FOSTER:    That does not surprise me.

7                DR. KASS:     Well, I mean, you are a genial

8    sort, and I think you won't -- I mean, one of the

9    things that one has to remember in this conversation

10   is that wonderful as the stem cell approach is from

11   whatever source to the treatment of these diseases,

12   that is not the whole area here also.

13               And that the gene therapy is not the whole

14   story as well, and there are preventive measures, and

15   there are all kinds of other things.         I mean, the

16   conversation, because we are taking it up, gives it a

17   certain type of dramatic focus and concentration.

18               But for the people who work in clinical

19   medicine, they know that this is -- that there are

20   lots of ways to try to skin this cat.    But I wanted to

21   ask a couple of -- to make a comment, and then ask a

22   couple of questions.

23               You have talked understandably and very

24   welcomely to us about your own very exciting work.
                                                                161

1    There is a great deal of skepticism about many of the

2    published works in using adult stem cells.

3                  And   unfortunately,    for   better   and   for

4    worse, these reports are caught up in the political

5    controversy that now surrounds us, with people on both

6    sides having a stake in either making the results on

7    one line of work seem better than the other, precisely

8    because they are wed to an either/or choice.

9                  Can   you,     abstracting    from     all   the

10   political considerations, and the various axes that

11   various people are grinding on these poor cells, can

12   you say anything at all generally about the kinds of

13   initial reports of a clinical sort that we have had

14   with alleged adult stem cells?

15                 Because   at    least   according      to    some

16   accounts, these have been very exciting, and yet there

17   is a great deal of skepticism about whether these are

18   in fact stem cells that are producing the results.

19                 Can you tell the council anything at all

20   about how we should at the moment regard the news that

21   is coming out to us in this area?            How should we

22   receive it?

23                 DR. VERFAILLIE:     There have been several

24   publications that came out over the last 1 or 2 years

25   now, where investigators or clinicians have looked at
                                                                      162

1    individuals who were transplanted with classical bone

2    marrow transplantations, and looked in tissues outside

3    of the hematopoietic system to ask whether bone marrow

4    derived   of   donor-derived       cells   could   be    found     in

5    different tissues.

6                   And the reports that have come out have

7    indicated fairly significant levels of contribution to

8    certain tissues, meaning they have found cells in the

9    heart, and they have found cells in skin, gut, liver,

10   and so forth.

11                  And we really have not looked in the same

12   situation to see whether we can confirm these data or

13   not.    I know that some clinical groups have put in

14   doubt to some extent the degree of contribution that

15   has been reported, and it is not quite clear whether

16   the 5, 10, or 20 percent that has been quoted in some

17   papers is indeed actually going to hold up over time.

18                  I think there is some contribution, and

19   the    question   in   my   mind   still   is   how     clinically

20   important is it what investigators have seen or what

21   clinicians have seen currently.

22                  If you go strictly by the term of stem

23   cell plasticity, none of these studies really show

24   that it was a single cell, or it was a blood cell that
                                                                           163

1    gave rise to these tissues, and it might still be that

2    some contaminating cells were contributing to that.

3                     And   really      none    of   these    studies      have

4    shown that this has had any clinical impact on what

5    was going on in these patients.                  And so they didn't

6    really show that you restored function of the organ

7    that the cells were found in.

8                     DR. KASS:         I was thinking of a recent

9    report on the Parkinson's cases.

10                    DR.   VERFAILLIE:              Correct.       So     the

11   Parkinson's cases were -- and that is with fetal brain

12   tissues,      and   are    those    the     reports     that   you    are

13   referring to?

14                    DR. KASS:       Yes.

15                    DR. VERFAILLIE:           And so there has been a

16   series     of    patients        transplanted      in      Sweden     with

17   Parkinson's disease, where one team of investigators

18   in a non-controlled study, shows that implantation of

19   the fetal tissue brain -- fetal brain tissue into the

20   brain    of     patients    with        Parkinson's     disease      could

21   rescue     patients,       and    could     actually       correct    the

22   Parkinsonism.

23                    And actually have now done so for some

24   patients for more than 10 years.                    Now, these were
                                                                 164

1    highly selected patients, and done by a single group

2    of investigators.

3                  The same was done in the west in 3 or 4

4    institutions, and some patients got better and some

5    patients did not get better.        But I think that gets to

6    the proof of concept that if you have the right cells,

7    and if you can create the right cells, and if it is

8    from embryonic stem cells, or adult stem cells, or

9    from tissues itself, that there might be a way of

10   correcting Parkinson's disease.

11                 But there is again -- and I think it would

12   behoove us to really look carefully at exactly what

13   single cell or fused cells that we have to put into

14   the brains of patients with Parkinson's disease to try

15   to correct the disease, and not over correct it as it

16   was done in some of the patients in the U.S., where

17   they had more side effects from the therapy than they

18   initially had from their Parkinson's disease.

19                 And so even though there is an enormous

20   amount   of   pressure   on   all   of   us   with   stem   cell

21   research to try to come up with therapies yesterday, I

22   have been very, very cautious in telling people that

23   do the clinical work that you can't just go around and

24   take stem cells and put them in places in the hope

25   that they will work.
                                                                       165

1                    Because we will get into situations like

2    the   gene    therapy     field,    where    a    couple   of    awful

3    problems have popped up, and have actually halted the

4    clinical potential of these cells enormously.

5                    DR. KASS:    Could I follow that up, because

6    if there had been more time, I would have asked Dr.

7    Gearhart      this   question      as     well,   and   you     are     a

8    clinician who deals with patients that are also -- now

9    thanks to your new results, and I am sure that you are

10   getting lots of calls as well.

11                   There is an ethical dimension to this area

12   that worries not so much about where you get the cells

13   from,   but    how   we   deal     with    the    desperately     sick

14   patients looking for any sort of hope.

15                   And let me say flat out that in-part to

16   fend off the opponents, the people in the scientific

17   community and medical community, has to some extent

18   not been adverse to shall I say hyping the benefits

19   here and possibly even taking rather cruel advantage

20   of these hopes.

21                   And from what I hear from you, and from

22   what I hear from Dr. Gearhart, these therapies, there

23   are lots of problems to be solved before these things

24   will be made available.
                                                                        166

1                   And that is not to say that there isn't

2    this enormous promise, but what can you tell us, or

3    what    advice      would    you     give    us     about   we    could

4    responsibly speak about this promise without behaving,

5    let    me   say,    unethically      in    dealing   with   the   very

6    patients who are coming to us for help?

7                   And I think that's something that you have

8    probably faced directly, and whatever help you could

9    give us on that would be welcome.

10                  DR. VERFAILLIE:            Well, like Dr. Gearhart,

11   my e-mail and phone have a lot of messages on them

12   from patients locally, around the country, and around

13   the world who want to bring a child or a parent with a

14   certain disease, and want us to treat whatever disease

15   you can come up with.

16                  And we have to speak the truth, and even

17   though we are excited about the work that we have, and

18   for the work that people do in embryonic stem cells,

19   at this point it is a promise, and I don't think there

20   is any data to say that in the next 1 or 2 years we

21   will actually be in clinical trials with any of this.

22                  So     we    really    have     to    tell   patients,

23   families, and whomever, that currently we are trying

24   to cure mice, but a lot of mice have been cured with a
                                                                         167

1    lot of different things, and that doesn't necessarily

2    mean that it will translate into humans.

3                      And so we need to do the regular science

4    that needs to be done to come up with a therapy that

5    is    both    potentially       useful    and     for     certain    not

6    dangerous.

7                      And so that the last part of that whole

8    thing is really where everything sits.                     And so we

9    could go ahead and do things now, but then run into

10   major,      major   complication      issues     which     would    make

11   patients way worse off than they started out.

12                     You   could     argue      that       bone     marrow

13   transplantation, there was not a whole lot known when

14   the first bone marrow transplants were done, and that

15   is before I started in bone marrow transplantation,

16   and    probably     some    patients     didn't     fare    that    well

17   either in the beginning.

18                     But people ultimately still have to learn

19   by doing it in humans, but we have to learn as much as

20   we    can    in   culture   dishes,      mice,    rats,    and   larger

21   animals before we proceed with therapies for things

22   that are not immediately legal.

23                     And so it is not because you are diagnosed

24   with Parkinson's today that four months from now that

25   you will die from your disease, which is different if
                                                                              168

1    you have a acute leukemia, where there is really no

2    other solutions.

3                      And so I also think it will have to be

4    graded depending on the type of disease that you start

5    treating.

6                      DR. KASS:           And I have one last question,

7    and I don't think we will have another opportunity in

8    this discussion, but this comes to Rebecca Dresser's

9    question about the costs, and how to think about this.

10   And also about the applicability.

11                     There was recently a meeting of the major

12   biotech    companies        in    Princeton, and         our     scientific

13   director,       Dick      Roblin,       was   there,     and     they    were

14   discussing       among     other       things    the   question     of   the

15   solution     of     the    immune      rejection       problem    from   all

16   these various things.

17                     And     all    of    the ones    that    were present

18   there     are     putting       their     research      money    not     into

19   somatic      cell       nuclear       transfer    to     deal    with    the

20   rejection problem, but into other means, for a reason

21   that would have never have occurred to me until it

22   came back from this meeting, which is to say that if

23   you   have      highly individualized treatments, case                     by

24   case, that at least under present regulatory systems,

25   if you call these things products, each one of them
                                                                                  169

1    has to be approved independently by the FDA before it

2    can be used.

3                     And so the question is whether or not --

4    and     in     partly       thinking       about      the     cost     and   the

5    scalability, and the things that might make things

6    universally applicable, doesn't it make sense more to

7    be    thinking        more    in    terms      of   cell      lines,    whether

8    embryonic or adult, and that could be made universally

9    applicable, rather than trying to continue to think

10   each person, his or her own replacement, given these

11   practical problems of scale and product approval?

12                    I     am     not       sure   that     the    question      was

13   clearly put, but it bears upon the efficacy of this in

14   terms of long term clinical use, and the questions of

15   cost.

16                    DR.     VERFAILLIE:             Ideally,       it   would     be

17   personalized therapy, and so you would create cells

18   that are completely compatible with the person that

19   you need to treat, except again in situations where

20   there     is     an     autoimmunity           issue,       which    makes     it

21   complicated.

22                    And         if    it    is    an     autoimmune        problem

23   starting out, then cell therapy is probably not the

24   best way to go about doing this.                    For instance, Type-1
                                                       170

1    diabetes would come to mind, where there is really a

2    rejection of your own islet cells.

3                I think the costs -- and I spoke to that

4    just a little bit before -- of creating everybody's

5    own cell line will in the long term will be extremely

6    high, and it will not be a therapy that is suitable

7    for acute events.

8                So if you have an acute stroke, or if you

9    have an acute heart infarct, and you try to correct

10   that, there is no way that you can clone ESLs to

11   correct that, or you could create MAPCs to correct

12   that within the next one or two weeks.

13               It just takes too much time to try to do

14   this.   Then you could argue, well, I will store our

15   own MAPC cell lines or own ESL lines just in case we

16   need it, which definitely I don't think is financially

17   tenable.

18               So even though the ideal situation would

19   be to be able to make everybody's own cells, and I

20   think in the long term if the cell therapies       are

21   proven to be, for instance, very useful in patients

22   who have a severe MI that you can actually correct

23   them almost immediately after the MI has occurred, or

24   within the next few weeks after it has occurred, it

25   almost has to be done on an allogeneic basis.
                                                                      171

1                     And in that case, trying to come up with

2    wise ways of making the cells acceptable to the vast

3    majority    of    patients,    whether    it    is    multiple   cell

4    lines and a minimum amount of immunosuppression, or

5    establishing partial chimerism by creating both blood

6    cells and heart muscle cells from the same cell lines,

7    for instance, would be one way to get around that.
8

9       DR. KASS:           Thank you very much.          Thank you very

10   much for a wonderful presentation, and a very generous

11   and full response to our questions.              If we might take

12   the liberty of just contacting you with some other

13   things.

14   I know that your e-mail is full, and we will try to

15   add very little, but as we go along, we might have

16   some additional things.

17                    DR.    VERFAILLIE:      That   would    be   great.

18   Thanks.

19

20   DR. KASS:    Thank you very much.          Members are asked to

21   go immediately from here to the other room, where they

22   want a group photo, and the four or five of us who

23   have not yet posed for our individual mug shots, are

24   asked to stay.         I think lunch will be served there.
                                                            172

1                We will reconvene here shortly after 1:30,

2    and let's say about 1:35 or 1:40.

3                (Whereupon,   at   12:28   p.m.,   a   luncheon

4    recess was taken.)

5

6

7

8

9

10

11
                                                                                       173

1                   A-F-T-E-R-N-O-O-N               S-E-S-S-I-O-N

2                                                                      (1:41 p.m.)

3                       DR. KASS:          Well, if I sing a song, or make

4    some     announcements,           maybe        we    will       get        the    full

5    numbers, but this is the third of our three sessions

6    on     stem   cell        research,         having     spent      the        morning

7    hearing two presentations on the science.

8                       And we now turn in this session to ethical

9    questions      in    stem        cell    research,         and    we       are    very

10   fortunate to have as our guest Professor Gene Outka,

11   who     is    the        Dwight       Professor       of     Philosophy           and

12   Christian Ethics at Yale University.

13                      And     for    a     long    time      one     of       our    most

14   careful students of the ethics of biology and medicine

15   among many other things.

16                      Apart from our interest in the merits of

17   the case, a paper written on a subject of concern to

18   us, I have confessed in the chairman's cover letter,

19   in a sentence which has a missing word, that I have an

20   additional purpose in mind here, namely as just as

21   those of us who are not experienced in science, need

22   practice      in     grasping         the    concepts       and       methods       of

23   scientific      analysis,          so       those    of    us     who       are   not

24   experienced         in    ethics       would    need       some    practice         in

25   working       with       the     concepts       and       ways        of     ethical
                                                                     174

1    analysis.       And Professor Outka's work is nothing if

2    not careful, analytical and disciplined, and we are

3    very thankful that he could be with us to discuss his

4    paper.

5                    All of us have had a chance to read it,

6    and I exhorted you to read it more than once, and

7    there is a lot packed in it.            And Professor Outka is

8    going to lead off with a few remarks, after which I

9    have asked Michael Sandel to make comment that would

10   open our discussion.      Thanks very much, Gene.

11                   DR. OUTKA:      Well, it is a great honor for

12   me to be here, and I enjoyed sitting in enormously in

13   the   morning    sessions,      and   noted   that   although   the

14   focus was on scientific matters, moral matters also

15   arose from time to time, as when Dr. Gearhart told us

16   that he doesn't give the same moral status to the

17   embryonic entity as he does to the fetus.

18                   And I think that illustrates one of the

19   claims that I actually make in the paper, which is

20   that on this subject, whether we like it or not, we

21   all have to be moralists in one way or another; that

22   certain moral determinations are unavoidable.

23                   And   in-part    that   is    because   the   moral

24   positions that we take have such direct and sometimes
                                                                               175

1    colliding implications for the policy and political

2    recommendations that we make.

3                   And I contrast that with certain other

4    cases where you could have some theoretical debates

5    and disagreements might abound on that level, but you

6    could   when      you    turned        to    practical      and    political

7    matters,    you     could       come    to    some   modus        vivendi    or

8    something      of       the     sort,        where    the     theoretical

9    disagreements           don't     translate          into     necessarily

10   practical political disputes.

11                  That is not the case with this subject I

12   contend, and so we all have to be inclined to engage

13   in moral reflection, and although moral reflection has

14   its own esoteric features in the hands of at least

15   some,   I    think        that     this       session       may     be    more

16   egalitarian in a way, because I, like Samuel Johnson's

17   dictum, that we are perpetually moralists, but we are

18   geometricians only by chance.

19                  And by that I take him to mean that moral

20   matters, that there is a fundamental equality about

21   our   reflection        on    moral     matters,     and     it    does     not

22   require a special talent in the same way.

23                  So that then leads me to say a few things

24   about this paper, which we are going to discuss.                                I

25   tried to do several different things in it, and I
                                                                  176

1    tried to give some kind of an account of some of the

2    major points of disagreement, and I have a spectrum of

3    views from the right to the center, to the left.

4                  And I myself then plum for a particular

5    region of the center, and along the way though I do

6    try to show how debates about abortion and debates

7    about stem cell research converge and diverge.

8                  And finally I propose a nothing is lost

9    principle, and let me say a little more about that,

10   but   I   think   probably   the   most   economical   way     to

11   proceed is simply to indicate for you some of the

12   normative conclusions that I put forward in the paper.

13                 And not tarry over the questions about

14   whether I do justice to those either more conservative

15   than I am, or more liberal than I am.          Spokespersons

16   for both positions can speak for themselves later on.

17                 So let me just then lay out some of the

18   claims that I make, and that will get us started at

19   least.    I make some claims about the status of human

20   life from conception forward, and I argue that once

21   conceived each entity is a form of primordial human

22   life that should exert a claim upon us to be regarded

23   as an end and not a mere means only.

24                 And I say that it is one thing to allow

25   that we need not yet ascribe full moral standing or
                                                                        177

1    equal protectibility to embryos.               That is to say, I

2    deny that abortion and embryonic stem cell research

3    are morally indistinguishable from murder.

4                  But I claim on the other hand that it is

5    another thing to instrumentalize embryos through and

6    through when what we intend in the actions we perform

7    exhaustively concerns benefits to third-parties.

8                  And I take that to be one indication of

9    sheer instrumentalization, where the actions that we

10   perform we can only justify, and justify exhaustively

11   by virtue of benefits to third-parties.

12                 That is to say that I deny that abortion

13   and     embryonic    stem        cell   research     are        morally

14   indifferent    actions      in    themselves    to   be    evaluated

15   wholly by the benefits that they bring to others.

16                 I then go on to conclude that to conduct

17   research on embryos that creates them in order to

18   destroy them clashes directly with the judgment that

19   entities conceived have irreducible value.

20                 So that is on the one hand.            I want to say

21   that the case for sheer instrumentalization is to be

22   resisted, but on the other hand, I also think that we

23   don't     confront    a      single      either/or         as     some

24   conservatives and some liberals suppose, to the effect
                                                               178

1    that   we   should    forbid   all    embryonic    stem   cell

2    research, or we should permit it all.

3                 I    consider     instead     a   more   nuanced

4    possibility, or at least I think it is more nuanced,

5    where we may distinguish creating for research and

6    only employing for research.

7                 And the latter of employing for research

8    allows us to consider in vitro fertilization as a

9    practice in our culture, and employing for research

10   connects with the datum of discarded embryos, where I

11   want to say that the original creation of embryos has

12   a non-instrumentalist rationale, namely the promotion

13   of fertility.

14                So      that   what     we   intend   does    not

15   exhaustively concern benefits to third parties.            But

16   yet the aftermath allows us to pursue benefits to

17   third parties when we may do so without from the start

18   creating in order to disaggregate.

19                And the way that I try to speculate about

20   the pros and cons of this conclusion is to invoke the

21   nothing is lost principle, which I think illuminates a

22   morally significant distinction between creation for

23   research and employment for research.

24                The nothing is lost principle says that we

25   may -- that although it takes the prohibition against
                                                                            179

1    murder seriously, it allows two exempting conditions.

2    The first is that the innocent -- that some innocent

3    will    die   in    any    case,      and   the     second     exempting

4    condition is that other innocent life will be saved.

5                   And applying that to the matter at hand, I

6    say that we cannot choose whom we save in the case of

7    discarded embryos.         They will die if we do nothing.

8                   And we cannot save them by killing others

9    or letting others die.                Yet, we may save others by

10   virtue of the research.               And yet on the other hand,

11   and why this remains incurably in the middle, while

12   the nothing is lost principle permits attention to the

13   possible benefits to third parties from research on

14   discarded     embryos,     it    does    not   permit       the   concern

15   about the status of embryos to recede to a platitude.

16                  And where such concern never has efficacy

17   and can always be trumped, and that is one of my tests

18   about   saying      that    a    commitment       to   in    this      case

19   embryonic life is serious only if it trumps something

20   whenever there is a conflict.

21                  It    does       not     have   to      trump      on    all

22   occasions, but it has to trump on some occasions.                      And

23   where I want to say it trumps is where it disallows

24   the creation of embryos only and exclusively for the

25   sake of, and in order to, disaggregate them.
                                                                  180

1                  I speculate on some of the difficulties

2    that this position generates and trying to face those

3    I hope honestly.       Some of the difficulties I regard as

4    more demanding than others, but I do rehearse some of

5    them.

6                  But I think it would take us too far a

7    field to review those now.          So let me just content

8    myself with having summarized that part of the case.

9                  DR. KASS:     Thank you very much.          Michael

10   Sandel will lead us off with some prepared comments.

11   Thank you.

12                 PROFESSOR SANDEL:          Well, let me first of

13   all add my thanks for really a fine paper that has so

14   many virtues of the best work in moral philosophy, and

15   its close reasoning, and its careful reasoning, and in

16   it   directing   our    attention   to    some   really   central

17   moral questions.

18                 And it also has, the paper does, and the

19   proposal of the appeal of staking out a middle ground,

20   of   trying   to   find     an   alternative      to   either/or

21   positions, that it exudes the spirit of compromise,

22   which is appealing in and of itself.

23                 And more than that, the kind of compromise

24   that it offers has a certain kind of intuitive appeal,

25   which is faced with these hard moral questions about
                                                                         181

1    the status of embryos, it is on the other hand the

2    goods to be had from research and possibly curing

3    disease.

4                  And the intuitive appeal is to say, well,

5    the spares, the excess embryos left over from IVF

6    clinics, they are going to die anyhow, and so we may

7    as well get some good use out of them and do some

8    good.

9                  But    we    shouldn't   therefore         consider     it

10   morally permissible to create for the sake of the

11   research or curing of diseases new embryos.                We should

12   just use the spare ones and that is the nothing is

13   lost principle.

14                 There is something very appealing about

15   that compromise and intuitively persuasive.                But since

16   I don't find it persuasive, I want to see if I can

17   press   a   little   bit     and   offer   a    concrete    case      to

18   illustrate why I don't think the principle works, or

19   is persuasive.

20                 The    first    thing to     notice    --     and   this

21   struck me I think only maybe in my second reading of

22   the paper -- is that the distinction, the crucial

23   distinction is not as we might think from our common

24   discourse    about   these     subjects,       between    fertilized

25   eggs left over from the -- well, the distinction isn't
                                                                         182

1    between the IVF fertilized eggs, or embryos, on the

2    one hand, and cloned ones on the other.

3                    To    the    contrary,   the    morally      relevant

4    distinction here cuts across the distinction that we

5    are familiar with between the ones that come from the

6    IVF clinics, and the ones that are created as clones.

7                    Because the crucial distinction is why the

8    embryo was created.           So if we imagine an embryo, a

9    cloned embryo, created for reproductive purposes, and

10   then we consider it spares in that process, it would

11   be all right to do research on those cloned ones,

12   provided    that      they   were   created    for    the    sake     of

13   reproduction.

14                   But it wouldn't be all right to use cloned

15   embryos created for the sake of research.                   Likewise,

16   it would be all right to use embryos created with

17   sperm fertilizing an egg in an IVF clinic, provided

18   that it was created for the sake of reproduction.

19                   But it wouldn't be all right to use an

20   embryo created when a sperm is brought together with

21   an egg in sexual reproduction in a clinic if the

22   purpose    of   the    clinic   bringing      the    egg    and   sperm

23   together was to create an embryo for research.

24                   So the key here, and what is carrying the

25   moral weight, is not how the embryo was created, but
                                                                          183

1    why.      Scientists      may    use    excess     embryos,     however

2    created, provided that they were created for the sake

3    of reproduction.         But scientists may not use embryos

4    created     for    the    purpose       of   research     or     curing

5    diseases.

6                     Then    the    question      arises    why    or    the

7    reason,     or    the    motive       for    creating    the     embryo

8    determines whether it is permissible to use them for

9    research into diseases.

10                    Now that is the heart of the question; why

11   the    motive     matters,      and    why   the   motive      for   the

12   creation makes a moral difference.                  And the way to

13   explore this question would be to put aside cloning

14   altogether.

15                    Let's imagine two cases; of traditional

16   sexual creation of an embryo, or in a clinic, or in a

17   lab.    In case one, a woman comes to an infertility

18   center and donates some eggs because she wants to help

19   infertile couples have a genetically related child.

20                    And the clinic brings together her eggs

21   with donor sperm and creates some embryos, some of

22   which are implanted, and some of which wind up being

23   spares.

24                    In case two, a woman goes to a clinic or

25   to a lab, and donates eggs for a different reason.
                                                                           184

1    She donates them because she wants to support stem

2    cell research to cure Alzheimer's and Parkinson's.

3                     Her eggs are brought together with donor

4    sperm,    and    made     available    to    scientists         who    are

5    engaged in this research.

6                     In both cases, the motive of the woman who

7    contributes or who donates the eggs is to advance a

8    worthy    end;     helping    an     infertile         couple   have        a

9    genetically      related     child    in    the   first     case,      and

10   advancing scientific research in the other.

11                    And in both cases, she contributes knowing

12   that at least some of the embryos created from her

13   eggs     will    be     sacrificed,    will       be     discarded      or

14   destroyed.

15                    Now,    according    to    the   nothing       is    lost

16   principle, what do we say about the availability of

17   these two embryos, or sets, or batches of embryos for

18   research?

19                    Well, the nothing is lost principle in the

20   paper tells us that it is okay for scientists to

21   extract stem cells from the first batch, but not from

22   the second.      And the question that I have is why.

23                    The answer that the paper seems to give

24   is, well, in the first case, they are spares.                         They
                                                                          185

1    are excess embryos.           But then it is not so clear to

2    me what counts as spare.

3                  Well, strictly speaking, a spare is an

4    embryo not needed for reproduction that is going to

5    die anyhow.      So we may as well use it for some good.

6    But by that definition of a spare, both batches of

7    embryos are spares.

8                  Once      they    exist,    they     both      meet    the

9    nothing is lost principle.               It is true that both

10   batches of embryos that we have here are going to die

11   otherwise, and we might as well get some good use out

12   of it.

13                 So that can't be -- well, maybe that is

14   too limited of an account of what you mean here by

15   spare embryos, because by that definition they would

16   both be spares, both batches.

17                 So maybe there is a further condition of

18   an embryo being a spare embryo; namely, that it had

19   been   created    in    the    first   place     for   the    sake     of

20   reproduction.     That would limit us to batch one.

21                 But      then    the   question    is    whether      that

22   condition adds any moral relevance or interest.                      The

23   idea must be that the intention of the donor confers

24   some morally relevant difference.
                                                                           186

1                   Moreover,       a    morally    relevant       difference

2    that somehow filters all the way down to govern what a

3    scientist    may     morally       do.     Well,     what    could    that

4    difference be?

5                   How     could       the     motive,     the    different

6    motives in these that led to the creation of these two

7    batches of fertilized eggs, or of embryos, how might

8    that   work?       Why   would       the    motive     make    a     moral

9    difference?

10                  Well, there are at least two possibilities

11   that I see from the paper.               Maybe the motive makes a

12   difference in the moral status of the embryos that

13   result.     Maybe it makes a difference therefore in the

14   respect that the embryos are due.               But why would that

15   be?

16                  How does the different motive in the two

17   cases confer different moral status on the embryos in

18   batch one than in batch two, such that the ones in

19   batch one are properly open to use, to be sacrificed

20   for a worthy scientific end, but not the ones in batch

21   two?

22          There doesn’t seem anything different in the

23   moral status of the embryos in batch one and batch

24   two. Well, maybe the difference then isn’t in the
                                                            187

1    moral status of the embryos that result from these

2    different motives.

3          Maybe the difference is in the way that the

4    scientist who would do the research is complicit in

5    the destruction of the embryos that is a necessary

6    feature of the research. But how does the motive that

7    the donor had in creating the two batches change the

8    degree of complicity of the scientist?

9          And here I am drawn to our Footnote 12, which

10   cites our colleague, Gil, in a question that he put,

11   which I think is a perfectly relevant question here if

12   you are trying to work out some difference in the

13   complicity.

14         Just    because   there   are   some   embryos   that

15   somebody else has decided to destroy or to discard,

16   why does that remove the complicity of the scientist

17   who does the killing, and Gil’s example, who is cited

18   in the paper, seems to me to be a very good one.

19         If the Nazis decided to gather people in the

20   concentration camps and had determined that they be

21   killed, it wouldn't -- that fact that they were going

22   to die anyhow, wouldn't justify a doctor coming and

23   yanking out their organs to save some innocent people.

24                 He would not be less complicit or she,

25   that doctor, in doing or in yanking out their organs
                                                                         188

1    to do a good thing simply because somebody else had

2    decided that those people would already be killed,

3    regardless of how you regard the moral status of the

4    embryo.

5                  It seems to me the degree of complicity

6    isn't affected by the motive of the person who created

7    the embryo in the first place.             Well, the only other

8    possible answer that I can think to the question why

9    does   the   motive    of    the   donor    confer   some    morally

10   relevant difference on these two batches, is -- well,

11   maybe to recur to the underlying intuition of the

12   paper, which is that embryos should be treated as

13   ends, and not only as means.

14                 And therefore to sacrifice excess or spare

15   embryos in connection with IVF is morally permissible,

16   because the donor didn't know which of the embryos

17   created would be sacrificed, i.e., treated as a means,

18   even though the donor knew that some would be.

19                 But     even   if    that    marks   out   a   morally

20   relevant difference for the donor, and the donor's

21   willingness    to     sacrifice    embryos    for    the     sake     of

22   various ends, it is not clear how this makes the

23   embryo that results more open to use by the scientist.

24                 So my question is going back to these two

25   scenarios, these two batches, created for different
                                                              189

1    motives, to test my motive matters, is what moral

2    difference does the motive make.

3                 DR.   KASS:    We   have    to   decide   on      a

4    procedure it seems after a wonderfully rich comment

5    like that.   The only fair thing to do is to ask Gene

6    if he would like to respond now or later.

7                 DR.   OUTKA:   Well,    I   think   it    was     a

8    wonderfully rich comment, and probably since it was a

9    rather complicated one, it might be best at least to

10   maximize the chances that I will forget less of it if

11   I go ahead and respond now rather than wait, because

12   there are a number of points that come up.

13                And I thank you very much for your care in

14   putting these questions to me.     I guess I don't really

15   want to use as you suggest -- and I don't use I think

16   the language of motive.      There is a wide question

17   about why the embryo is created, but I don't think

18   that is satisfactorily accommodated by calling it a

19   motive.

20                What I wanted to do was two things.               I

21   wanted to take seriously the notion of the injunction

22   that comes to us in religious traditions, but also in

23   some philosophical ones, above all, Kantian ones, that

24   treating people as ends and not merely as means.
                                                                             190

1                    And I wanted to say that that generates a

2    certain case for inviolability, and so I connected

3    that injunction to the ethics of killing.                             So the

4    first thing that we are talking about I think is more

5    the   morality      of    actions,     rather    than      the   morality

6    simply of motives.

7                    And I want to say that certain actions may

8    be licit if one can say that the rationale for

9    -- let's say in the case of IVF clinics, being in the

10   mess that we are in with respect to them doesn't have

11   to do with actions that we ourselves perform.

12                   We are actually dealing with the after

13   effects    of   an   entire        industry,    and       so   that    would

14   already    distinguish        the      status        of   what    we     are

15   contemplating there from the status of contemplating

16   a direct action ourselves when we do X in order to do

17   Y.

18                   And I want to say that a prime case for

19   treating an entity as instrumental through and through

20   is when we do X in order to destroy them for the sake

21   of the benefits that destruction will bring to third

22   parties.

23                   I    want         to   say     that       that    is        an

24   instrumentalist          action    through     and    through.         So     I

25   would prefer to use the language of ends and means,
                                                                               191

1    and    the    morality     of    actions,         and   specifically      the

2    prohibition against killing, rather than I think the

3    language of motives.

4                    And which does not seem to me to quite

5    capture those points.                Now, in regard to your very

6    interesting example, of case one and case two, it

7    would be the case that if a woman donates eggs for

8    reproduction, she there is donating her eggs for an

9    end that isn't menial.

10                   I mean, there she is donating her eggs for

11   the sake of a couple who want a child, and so nothing

12   that the couple contemplates, or nothing that she does

13   contributes      to    a    case      for    creating      in     order     to

14   destroy.

15                   Whereas, if she gives her eggs to support

16   stem cell research -- and that is her only reason, so

17   that she is giving her eggs in order to do that --

18   there    it    seems   to       me   that    she    runs    the    risk     of

19   violating the thing that I am objecting to, which is

20   creation in order to destroy.

21                   So the relevant fact is not simply that

22   they are both spares.                The relevant fact has to do

23   with    the    morality     of       the    two    different      kinds     of

24   actions.
                                                                        192

1                      And where the ends have to then be also

2    distinguished, and you say that both ends are worthy.

3    One    is   to    help    a   couple,   and    one   is    to   promote

4    research.        But I am precisely objecting to the second

5    kind of so-called worthy end if it means that you may

6    directly create a life in order to destroy it.

7                      That seems to me to be a trumping action;

8    that is to say, the objections against a trump, the

9    good   aim   of       promoting    research.      Whereas,      nothing

10   about helping a couple involves a creation in order to

11   destroy.         So it is not subject to the same kind of

12   objections.

13                     Now, you also then list some possibilities

14   about how these different cases might be distinct.                       I

15   think the batch one and batch two -- I hope that I

16   have    given     a    different    account     of   why   I    make     a

17   distinction between those two cases.

18                     Your reference to Gil Meilaender is a very

19   important        objection    to   me   in    correspondence     about

20   whether or not nothing is lost allows to much or

21   permits too much.

22                     I strain there, and I grant that I strain,

23   but what I want to argue is that in the case of

24   embryos slated for destruction, and who are frozen in
                                                                193

1    perpetuity, or eventually to be discarded, we have a

2    peculiar condition of perpetual potentiality.

3                   And that distinguishes them from some of

4    the other possible uses of nothing is lost, which I

5    disallow.    So there the argument would be that they

6    are   the   peculiar   features    of    entities   that   are

7    characterized as having perpetual potentiality that

8    distinguishes them.

9                   That is not certainly an adequate reply,

10   but that would be the shape I think of my general

11   response.

12                  DR. KASS:   Michael, please come back and

13   maybe one more round would help, and other people

14   would like to get in on this.

15                  PROFESSOR SANDEL:        Well, there are two

16   issues here.     The last point was an attempt to show

17   that in the first case the woman who donated an egg to

18   help a childless couple, that her act was morally

19   permissible.

20                  Whereas, the second woman's act was not

21   morally permissible because it instrumentalized the

22   embryo in a way that the first one didn't.          Now, that

23   is one issue, and I would like to come back to that

24   issue maybe later.
                                                                                       194

1                       But even if you are right about that, it

2    still     would         be    true        that     the       nothing     is       lost

3    principle, from the standpoint of the scientist, must

4    regard    both       batches         of    embryos       as     spares       in    the

5    relevant sense that they are going to be discarded or

6    destroyed anyhow, and why not derive some good from

7    them.

8                       So    even        if     you       made     out     the     first

9    distinction between the acts of the woman donor, and

10   there are questions about that, but independent of

11   that, still how does that limit or change the scope of

12   the scientist's responsibility, such that -- there are

13   certain eggs or the eggs in batch one, because they

14   were not conceived instrumentally, are open to use.

15                      Whereas,          the    eggs        in     batch    two,       the

16   embryos       in   batch          two,    because       they    were    conceived

17   instrumentally, are not open to use.                           Why is that?

18                      DR. OUTKA:             Well, the key thing there I

19   think     I    think         is    that     I     was    talking       about      the

20   rationale of in vitro fertilization clinics by and

21   large,     and      rightly         or     wrongly,          characterize         that

22   rationale as being able to sort of claim that.

23                      Their      dominant          aim     was    to    address       the

24   problem of infertility, and not to provide embryos for

25   research.          That is the overall generalization, and I
                                                                               195

1    know that there are a lot of questions to be raised

2    about that, and at the very end of the paper, in the

3    last version of the paper, I raise some of those

4    questions myself.

5                    But nonetheless I would stick to that.                      So

6    I   would    think    that      your    second       case,    your      second

7    batch, would not come up very much.                          I mean, I am

8    obliged to you for thinking that it might.                         I guess I

9    was talking about in vitro fertilization with that

10   overall rationale.

11                   You       are   talking       about   women      who     would

12   donate      their     eggs      simply        to   support       stem     cell

13   research,      and    they      would    do    that   independently         of

14   whatever the scientist did.

15                   And I would agree that in such a -- and I

16   think    they       are    pretty       rare       cases     though,      that

17   scientists would not be complicit.

18                   PROFESSOR        SANDEL:           They    are   rare     only

19   because IVF happened to get going sooner, and it has

20   generated a hundred-thousand of them.                        But once stem

21   cells get going, there is no reason to think that

22   there won't be a hundred-thousand of those out there.

23                   DR. OUTKA:        I doubt it very much.              I mean,

24   there    are    lots       of    questions         actually      about    the

25   pressure     placed       on    women    to    donate      eggs,    and   the
                                                                         196

1    morality of egg donation is actually I think a really

2    important      subject      that   has   not     been   discussed     by

3    ethicists.

4                    But the important point here is that since

5    you don't have such a class, what I am objecting to

6    are     researchers,     scientists,       who    become    complicit

7    because they themselves do the creating.

8                    PROFESSOR SANDEL:           Through cloning, but

9    morally speaking, what do you say about the case where

10   a lab takes or invites women to donate eggs, whether

11   it pays them or asks them to donate them for the

12   purpose of stem cell research?

13                   DR. OUTKA:         If it is inviting them, I

14   would have to look at that.                To the extent that it

15   takes initiative, to that same extent it becomes more

16   complicit, and therefore more subject to the objection

17   that I am raising.

18                   PROFESSOR SANDEL:           But you would agree

19   that from the scientist's point of view how it got

20   there, whether it was from someone who gave it for

21   reproductive purposes, or from someone who gave it for

22   stem    cell   research      purposes,     from    the     scientist's

23   point    of    view,   do    you   think    that    makes     a   moral

24   difference?
                                                                       197

1                DR.   OUTKA:      Well,    I   do    if       they    are

2    inviting a woman to donate eggs so that they may take

3    those eggs and fertilize them in order to destroy them

4    for the sake of, and so yes, then they are complicit.

5                PROFESSOR SANDEL:         Well, the lab.             I am

6    assuming the lab does and then the scientist goes and

7    gets the -- whether the scientist, or whether she goes

8    to the lab and says give me some of your spares from

9    reproductive donations, or says give me some of your

10   spares from people who actually wanted their eggs to

11   go to this purpose, do you think it is worse in the

12   second case for the scientist to do that?

13               DR. OUTKA:     I think it is worse whenever

14   there is an active role played in an action which I

15   regard as disallowed for reasons given.               Now, there

16   are a lot of nuances here, and I know that there are a

17   lot of conservatives who think as I say in the paper,

18   there will be some colluding going on between people

19   who run in vitro fertilization clinics, and scientists

20   who want spare embryos.

21               And   I   agree   that    there     is    a    kind     of

22   performative problem there, and I tried to discuss

23   that.   So I am not saying that there aren't shades

24   here, but the spirit of the paper is this.
                                                               198

1                   That we do have an action where we are

2    creating in order to destroy something, and that does

3    seem to me that it should give us pause.           It is not

4    the same, and it won't simply be justified by saying,

5    well, look at all of the third parties who are going

6    to benefit.

7                   If that is what we are saying about it,

8    and we are creating in order to destroy for that

9    reason, then let's say it very clearly.        But let's say

10   that    we   are   then   treating   some   entities   totally

11   instrumentally, and make no bones about it.

12                  That is the first part of the spirit of

13   the paper.     The second part is to say, all right, it

14   is the case that there are enormous benefits to be

15   derived from embryonic stem cell research.

16                  Let's see whether or not we can mount a

17   consistent moral argument that will allow us to draw

18   on some of those, but to keep some limits, so that we

19   are not simply tolerating anything, or losing all of

20   our criteria for distinguishing.

21                  That is the spirit of the paper.          Now,

22   some of these cases will involve as I say gray areas,

23   but I don't think that those gray areas by themselves

24   will invalidate that two-fold part of the case as

25   such.
                                                                          199

1                   PROFESSOR SANDEL:            Just a brief reply.        If

2    doing       something      to      help       a      third-party       is

3    instrumentalizing, then all of the embryos in batch

4    one   are    also    morally    impermissible         because   we   are

5    imagining     a     case   where      the     woman    goes     to   the

6    infertility clinic to donate her egg for the sake of a

7    third-party, for the sake of another couple having a

8    child.

9                   So that is doing a good thing for a third-

10   party, and so that is instrumentalizing isn't it in

11   just the same way as the second case?

12                  DR.    OUTKA:          But    there    is   no   killing

13   involved.     She is donating her eggs in order that they

14   may take those eggs and fertilize.                      That is life

15   enhancing.     This is as I said --

16                  PROFESSOR SANDEL:            Provided that there are

17   no spares that are destroyed.

18                  DR. OUTKA:       No.

19                  PROFESSOR SANDEL:             The issue arises only

20   because -- if it were a one for one, if there were no

21   spares, no excess, then the issue wouldn't arise.                      We

22   are talking about the woman making the donation to

23   help the third-party have a genetically related child,

24   knowing that there will be some fertilized egg, some
                                                                     200

1    embryos,   that    will    be    sacrificed,   discarded,      as     a

2    consequence of her doing that.

3                   DR. OUTKA:        But you know how long, and

4    perhaps too long in the paper, that I agonized about

5    precisely that recognition.          That that is a case where

6    we   foresee     under    present    circumstances     that     more

7    embryos will have to be created for promoting this end

8    of conception, and fertilization, than we would like.

9                   But we say that we foresee that, but we

10   don't directly intend it, and there is still a claim

11   that I think needs to be -- I would still want to try

12   to make, which is that there is a morally relevant

13   difference     between    foreseeing     the   inevitability        of

14   excess embryos, and lamenting that, and wanting it

15   over as soon as we can, et cetera.

16                  And creating again in order to kill, or to

17   destroy,   and    I   still     think   that   there   will    be     a

18   difference there.

19                  DR. KASS:        There is a long queue that is

20   prompted either by the paper or the comments.                 I have

21   Jim Wilson, Mary Ann Glendon, Alfonso Gomez-Lobo.

22                  PROFESSOR WILSON:         Let me begin with the

23   language of motive, because though he may not have

24   intended it, I think Professor Outka has in fact used

25   the language of motive on page 24, where he talks
                                                                  201

1    about creating an embryo exclusively for research, the

2    motive of the person.

3                 Or creating it exclusively for fertility,

4    the motive of the actor; and then again on page 35,

5    creating for research, motive, and creating for baby

6    creation, motive.

7                 I think it is well to get the word motive

8    out of our language.      I hope that Mary Ann Glendon

9    will forgive me if I use an inept legal analogy, but

10   in the criminal law, we don't ordinarily determine

11   guilt or innocence on the basis of the motive.

12                The man lies in wait to kill a woman, and

13   shoots her from a distance, and approaches closely to

14   make sure that she is dead, and finishes her off with

15   several bullets to the head.

16                We don't ask in the court whether he did

17   it to collect her insurance or to prevent her from

18   carrying on her experiments in dogs, since she happens

19   to be a biologist at a local university laboratory.

20                We might take motive into account in the

21   sentencing   decision,   but   that   would   be   up   to   the

22   probation officer.   It seems to me that to modify the

23   circumstance that Michael laid out for you and with

24   which we have been struggling, suppose now the woman
                                                                            202

1    donates   eggs      in     an    IVF   clinic,     and   they    are   all

2    fertilized.

3                      And suppose before picking the egg she

4    wishes,     she     does        what   I   think    is   in     fact   not

5    impossible, and may indeed be commonplace, she has

6    each fertilized egg tested for its likely hair color,

7    or intelligence, or sex, or whatever of the embryo

8    that will be produced.

9                      And having selected the egg she wants and

10   has it in place, she looks at the other people and

11   says kill the rest.              In fact, particularly kill those

12   two.   One is going to have Down's Syndrome, and the

13   other one is going to have cerebral palsy.

14                     Doesn't that put the IVF eggs in exactly

15   the same position as the eggs created by a woman who

16   has done it solely for the purpose of creating somatic

17   cell nuclear transfer for the purposes of biomedical

18   research?

19                     In fact, does it make it worse, because

20   now not only are the eggs that she has picked out with

21   the doctor's consent going to be destroyed, they will

22   not be destroyed in a way that will help anyone else.

23                     So that to me the leftover egg solution to

24   this problem doesn't work.                 The leftover egg solution

25   doesn't solve the moral difficulty.
                                                                        203

1                   DR. OUTKA:         Shall I try to respond to each

2    of these as I --

3                   DR. KASS:          Well, I think that these are

4    all solid, and --

5                   DR. OUTKA:         Oh, yeah, very solid.           I am

6    indebted to you all, and let me say though that I

7    think   the        statements     that   you     read    really     are

8    precisely about motive.

9                   Let's      maybe    use   the     language   that     is

10   closer to what I actually use in the paper, which is

11   intention rather than motive.            Now, I have always been

12   drawn   to    an    old   assumption     about    the    doctrine    of

13   double effect.

14                  I am not sure that it is going to work,

15   but I have always been fascinated with this claim, and

16   I think there are some cases where it worked, but it

17   doesn't always work.

18                  And        that     is    that     certain     action

19   descriptions        entail   certain     intention      descriptions.

20   Now, that is much closer to the timbre of my argument

21   than the language of motive, because what I want to

22   say is that an action, where you actually create in

23   order to destroy, if you describe that action, it is

24   hard to avoid identifying one intention.
                                                                    204

1                   And that intention is to destroy, and so I

2    don't -- I am going to continue to try to resist of

3    saddling me with the language of motives here, and I

4    don't think the statements that were cited really do

5    that.

6                   Let's think about intentions with respect

7    to actions more than about general motives.                    With

8    respect to your case, Professor Wilson, of all of the

9    eggs fertilized.      That it seems to me is -- I have

10   gotten a little bit of a bee in my bonnet about this.

11                  The suppose this or suppose that, as a

12   kind    of   test   for   measuring    the     adequacy   of     an

13   argument, this hypothetical case that you cite is I

14   think    not   at   the    moment     within    the   realm      of

15   possibility.

16                  So I am not sure that I have -- that I am

17   obliged to respond to it in precisely the terms that

18   you have set it out.       The fact of the matter is that

19   we do have a situation where one of these embryos is

20   going to be chosen to be implanted and brought to

21   term, and the others will not be.

22                  That is the datum that we are dealing with

23   in trying to make moral sense of, and I would have to

24   stick with that one, rather than speculate on all of

25   the eggs being fertilized, and then if she chooses
                                                               205

1    only one, rather than all of them, she is guilty for

2    what she does to the other.

3                I   think   that   changes   the   terms of   the

4    example so far that it is not any longer precisely

5    comparable as a test of what at least I want to argue.

6                DR. MCHUGH:        Leon, I have to interrupt

7    just for a second.      I just don't understand when you

8    say the intention, or any intention, is in order to

9    destroy.   Nothing is being made here in order to

10   destroy.

11               Will you explain that a bit further?                I

12   just got stuck on that.        In none of these cases is

13   anybody creating anything in order to destroy.

14               DR. OUTKA:     That is a very important point

15   and thank you for mentioning it.

16               DR. MCHUGH:    Sorry to interrupt.

17               DR. OUTKA:     No, no, no, I'm glad you did.

18   If I am wrong about this one, then a lot of things go

19   by the board, and I could be wrong about this one.              I

20   actually had wrung my hands about it quite often.

21               It involves a description of what is done

22   that does include my importing a kind of conclusion

23   about what is in effect going on that researchers

24   might not immediately consent to.
                                                                      206

1                   But it does seem to me that if you ask a

2    researcher why are you creating this entity, and the

3    answer is, well, I want to do something to it, which

4    will certainly kill it, but I am doing it for the sake

5    of third-parties.

6                   Then that seems to me to be an instance of

7    instrumentalizing it.           So the in order to destroy, or

8    in   order     to       disaggregate,     is   internal     to   the

9    description of the act I want to argue.                    Now, one

10   might try to get at the position by challenging that,

11   but it is hard for me --

12                  DR.      MCHUGH:     You    just   used    the    word

13   intention, that it was intention in order to destroy.

14   I mean, you had several intentions.

15   Perhaps,     and    I   might   accept    that,   but    there   were

16   several intentions involved here.              But you put it all

17   on the basis of in order to.

18                  DR. KASS:        Could I lend a hand on this?           I

19   mean, had you not raised the question, I would have at

20   some point.

21                  DR. MCHUGH:         I am sure that you would

22   have.

23                  DR. KASS:        But I think I can -- if I am

24   right, Gene, let me have a try.                I think the proper

25   way to state the intention is we create these embryos
                                                                           207

1    --    and   by   the    way,    I    don't    think   this    paper     is

2    primarily -- I don't think it is at all about somatic

3    cell nuclear transfer.

4                     I    think    the    question   really      should     be

5    taken up universally, regardless of how the embryos

6    come to be.       I think that Michael is right about that,

7    and this paper was written without even a reference to

8    it.

9                     But the researchers -- and there have been

10   people who have come forward to -- well, people have

11   come forward to donate their eggs and embryos for the

12   sake of research.         And the researchers who go to work

13   on that wouldn't say that we want these embryos in

14   order to destroy them.

15                    We want these embryos because we want to

16   use    their     stem    cells       for     understanding     or     for

17   treatment.       But it is the unavoidable and inescapable

18   entailment       of    that    intention      that    the    embryo     be

19   destroyed in the process.

20                    If there was some way in fact to get the

21   stem cells without destroying the embryo, people would

22   be delighted I assume.               And it seems to me that you

23   can make the same case as follows.

24                    This is not to say that the embryo is the

25   human being, but if you were to say that you too, out
                                                                            208

1    my heart in order to save my friend, Wilson, here who

2    needed a transplant.

3                     And that you weren't taking out my heart

4    in order to destroy me.             All you were really trying to

5    do was to save him, but if there was no way to do that

6    without destroying me, then that material fact of your

7    intent becomes embraced in the overall act with great

8    clarity.

9                     So   I     think       that   I    myself   would     not

10   describe this as saying to create it in order to

11   destroy    it.        I    would    create     it    in   order   to     do

12   something   else,         but   the     necessary     and    inescapable

13   entailment of which is the destruction, and therefore

14   you embrace that intrinsic aspect of the act.

15                    I think that is a better way to do it and

16   it doesn't try to gain mileage, if you don't mind,

17   from a more lurid expression that implies that the

18   people are in the destruction business because they

19   like destruction.          I don't think that is the flavor or

20   the intent.

21                    DR. OUTKA:         No, I take that as -- I will

22   regard that as a friendly amendment, and certainly

23   agree with it.            I think the reason that I used that

24   language    was       simply       to     underscore      that    it     is
                                                                               209

1    unavoidable that we can't ignore this as part of a

2    full characterization of the act.

3                   DR. KASS:         Sorry to have intruded.               I want

4    --

5                   DR. OUTKA:         That was very helpful.                 Thank

6    you.

7                   DR. KASS:         I have Mary Ann.

8                   PROFESSOR GLENDON:                Well, doctor, you were

9    very kind when you started out to adopt an egalitarian

10   approach, and suggest that we are all on a equal

11   footing with respect to the moral dimensions of these

12   very difficult problems.

13                  I must say that I feel a little backward

14   maybe because I am a lawyer, but I am still -- from

15   the very beginning, from my very first meeting, I have

16   been struggling with a problem that maybe you can help

17   me with.

18                  I    am     having       a    hard       time    seeing     the

19   difference between what is done -- forget about motive

20   and    intention,        but     what       is     done    in     in     vitro

21   fertilization, and what is done in creating an embryo

22   for research purposes, and let me explain why.

23                  I think that in both cases the procedure

24   is    done   with   full       knowledge         that   embryos    will     be

25   destroyed.      Now, many people, and not just at this
                                                                         210

1    meeting, but at previous meetings, many people have

2    said    that      the       difference      is    that     in      vitro

3    fertilization is done for a worthy end.

4                   And I think you or Professor Sandel said

5    to help couples with infertility.                 Well, we all know

6    that that is not quite right.               That very often it is

7    not    couples.         I   don't    know   whether      couples    are

8    predominantly      the       ones,    but    certainly      a      large

9    proportion.

10                  But leaving that aside, there are a number

11   of factors that I can think of that to my mind call

12   into question a casual assumption that what we are

13   dealing with here is such a worthy end that it would

14   justify the destruction of embryos.

15                  I will name some of them.            One is -- and I

16   am naming these as a constellation, and not that each

17   factor would be decisive in and of itself.                 But it is

18   an extraordinarily expensive procedure.

19                  It is highly uncertain in outcome.               It has

20   unknown long term health effects for women who are

21   subjected to massive doses of hormone injections, and

22   the    evidence    coming      out    now    is    suggesting       that

23   children born from this procedure may have an unusual

24   proportion of defects and disabilities.
                                                                     211

1                   And then finally as I said, it involves

2    creating an embryo with the certain knowledge -- or

3    creating embryos with the certain knowledge that some

4    of them will be destroyed.

5                   So I guess that my problem is that not

6    only that I wonder how that can be easily said to be a

7    worthy end, and then I guess more seriously, if we

8    accept   the   creation     of    embryos    with    the    certain

9    knowledge that they will be destroyed for purposes of

10   in vitro fertilization, doesn't it become or haven't

11   we   gone    very    far   down    the    road     indeed     toward

12   justifying     the   creation      of    embryos    for     research

13   purposes?

14                  DR. OUTKA:        Well, I thank you very much

15   for that question and I think it is forceful and

16   important.     And my perhaps only flagellations at the

17   end of the paper suggest that I feel its force.

18                  But for better or for worse, let me at

19   least sketch the lines of a reply, even though I don't

20   think this addresses all the things that need to be

21   addressed in your important set of objections.               One is

22   that I do think that there are two things in conflict

23   here.    One is infertility, and the other is excess

24   embryos, and we welcome neither.              I think that is

25   where we have to begin.
                                                                          212

1                  But I indicate that the datum leaves me

2    deeply disquieted, and I don't easily assume that it

3    is   simply   a   good.     I   agree     with    you    that   it     is

4    expensive and uncertain.

5                  It nonetheless is something, and I have

6    talked to a few people who have been through it, and

7    who have actually         -- it has resulted for them in

8    children, or grandchildren, and they are nonetheless

9    very thankful for it.

10                 But   I     suppose   the    spirit       again   of     my

11   approach is to say, look, this is a practice about

12   which there are many, many questions.                    But I am a

13   little uneasy with the grand -- now that a lot of

14   people are beginning to realize this, and are quickly

15   denouncing it, they often use the language of we.

16                 That we are responsible for this, and this

17   isn't like a contingent disaster.                This is something

18   that we have created by our own hands, and I would

19   register a slight disquiet with that, too, because I

20   don't think that we did it.

21                 I think that most folks who have the gift

22   of fertility don't worry very much about this.                  And so

23   this was developed         -- and I agree that we didn't

24   object to it, or resist it, but it was developed by

25   people with vested interest in it, both the infertile
                                                                         213

1    and     those    would       were    prepared   to   create     these

2    industries in order to address that problem.

3                     And now it is time it seems to me to air

4    whether     or       not    the   current   arrangements      can     be

5    justified, where you have 10,000 new spare embryos

6    being created every month, et cetera.                I mean, there

7    are a lot of questions that have to be asked.

8                     But I would also say that in the case of

9    nothing is lost, I do observe that nothing is lost

10   sometimes can be justified even in response to an evil

11   practice.

12                    I mean, there are some interesting cases.

13   For   instance,        in   Jewish   rabbinic   literature, about

14   acquiescing to the demands of the tyrant under certain

15   circumstances.         So you can invoke that nothing is lost

16   even when you don't think that the situation that got

17   you to here is admirable, or free from a certain

18   amount of evil.

19                    And I think that it is in that spirit that

20   I will want to say that however we got here, and

21   whatever we should do from now on, we do have this

22   datum     of     a     hundred-thousand      embryos   frozen         in

23   perpetuity, or slated for destruction, and we do have

24   to reflect about that.
                                                                 214

1                 I am not sure that is a very satisfactory

2    reply, but it is to evidence a good deal of sympathy

3    with your reservations, without I think ignoring that

4    one datum.

5                 DR. KASS:     Gil Meilaender.

6                 PROFESSOR MEILAENDER:      Gene, as you know,

7    I think it is a very nice paper, and as you also know,

8    that doesn't mean that I have no questions about it.

9                 And there are several things that I wanted

10   to ask about, but I want to stick with the nothing

11   more is lost, because it is central to your case, and

12   which I take it to mean -- I mean, if we were thinking

13   about what other kind of language would we use to

14   describe that, it means with respect to the particular

15   human   subject,   human   entity,   that    we    are   talking

16   about, that there is nothing that we can do that would

17   further diminish its life prospects.         I mean, that is

18   just by the nature of the case.

19                DR. OUTKA:     And also nothing much we can

20   do to help its life prospects.

21                PROFESSOR MEILAENDER:     Yes.       And there are

22   a number of analogies that we might think of.            I want

23   to come around to one of them in particular, but there

24   are a whole number; the condemned person, whose last

25   appeal has been lost; the irretrievably dying person,
                                                                215

1    who has only days to live; the permanently unconscious

2    person; the fetus in the process of abortion, or after

3    a decision for abortion has been irrevocably made.

4                 I mean, there are a whole number of such,

5    but let's take the anencephalic infant.            I take it

6    that there is nothing that you can do to further

7    diminish its life prospects.

8                 I don't know whether you are prepared to

9    think that under those circumstances that it may be

10   instrumentalized for various research purposes, but I

11   would like to sort of hear you reflect on it, since in

12   a certain way it almost seems to me that the case

13   might be stronger for that than for the spare embryo.

14                The spare embryo is sitting around waiting

15   to be instrumentalized because we made some choices.

16   The anencephalic infant is just there.       I mean, it is

17   not any choice of ours that got it there, and it

18   almost   seems   to   me   that   the   argument   would     be

19   stronger.

20                So I would just like to hear you reflect

21   on that, and see how you would think about that in

22   relation to the kind of argument that you make.

23                DR. OUTKA:     I know that is a first-rate

24   question, Gil, and since the anencephalic infant case

25   came up in connection with that suggested in your
                                                                 216

1    correspondence to me, I should have been more careful

2    probably in how I used it.

3                  My unsatisfactory response to this is that

4    I see the logic of saying that in some ways, since we

5    didn't have a role in bringing this about, there might

6    be greater warrant for using it.

7                  But I guess the context of my discussion

8    of that, of pairing them, was the context only of

9    saying that we are unable to do anything for them.

10   That there is a kind of cessation of the injunction to

11   treat them as ends rather than means.         We are limited

12   in what we can do.

13                 Our love can't affect very much, and I

14   really only wanted to make the comparison in that

15   connection.    I didn't want to sort of suggest that in

16   such cases that it would be quite all right to go

17   ahead then and use anencephalic infants for research

18   purposes.

19                 But   I   think    that   you   are   right     in

20   suggesting that that would have to be a loophole that

21   I would have to close.          I mean, I am worried about

22   this datum of the hundred-thousand spare embryos.

23                 I mean, there is a kind of overwhelming

24   fact to go back to the earlier question that I think

25   we need to say something about.          Is there anything
                                                                           217

1    that   we   are    doing    that     is    preferable       morally     by

2    freezing them in perpetuity.

3                   And my one place where I do not understand

4    the conservative concern about them is that I don't

5    know what people who don't want to destroy think they

6    are saving that is significantly different --

7                   PROFESSOR MEILAENDER:              Gene, can I just

8    make one suggestion?

9                   DR. OUTKA:         Yes.

10                  PROFESSOR          MEILAENDER:          We     are     not

11   embracing their death as our aim.

12                  DR. OUTKA:         Right.

13                  PROFESSOR MEILAENDER:             I mean, just as a

14   hypothesis,       might    that    not     be   what   someone      would

15   reply?

16                  DR. OUTKA:          They certainly could reply,

17   but the result of that is this peculiar situation of

18   perpetual potentiality, and so the witness looks very

19   marginal to me.       It almost looks like it doesn't have

20   very much to do with them.

21                  It simply has to do with a refusal to do

22   something that would bear on them, but at that point -

23   - and I would agree that my application of nothing is

24   lost, and it might have a slightly consequential sound

25   to it there.
                                                                                   218

1                        But I would be willing to risk speculating

2    about consequential steps there if there was something

3    to be done that might do some third-parties good.

4                        But in any case, back to your excellent

5    example.       Yes, I would have to say that I would have

6    to   be   careful,       and      if    the      logic   of    the       position

7    involved       my    saying      that    there      would     be     some     even

8    stronger case for doing something before the infant

9    died, then I would have to address that and modify the

10   position so that that consequence was not allowed.

11                       How I would do that is a nice question,

12   but I think I probably could devise a way to do it

13   that would not be unlike these other ways that I have

14   tried     to   devise       of    saying,        look,   this       is    a   very

15   special    case,       this      class      of    perpetual        potentiality

16   types.

17                       And it is not to be generalized from to

18   allow     nothing      is   lost       to    generally        be    invoked     to

19   harvest organs from the living, or from those whom the

20   government has condemned as criminals, or whatever.

21                       I do accept that there is a whole range of

22   those cases that I don't want to allow in, in my use

23   of the nothing is lost principle for the sake of

24   talking about embryos discarded.

25                       DR. KRAUTHAMMER:             Could I interject?
                                                                  219

1                DR. KASS:      On this point?

2                DR. KRAUTHAMMER:        Yes, on this point, and

3    a suggestion for an answer.         And that would be that

4    there is a fundamental moral difference in the status

5    of an embryo and of an anencephalic child.

6                The    child   is   a   full   human    being,       and

7    anencephalic or not, a comatose person is a full human

8    being, comatose or not, and we don't tear them apart

9    for their parts.

10               They are inviolable, and so I don't think

11   it is a terribly strong objection.          An embryo has an

12   intermediate, if you like, moral status, but certainly

13   is not the moral equivalent of a child or an adult who

14   is in a coma.

15               So I don't think that you open yourself up

16   under your argument, professor, to tearing up people

17   who are in comas or who are anencephalics.

18               DR. OUTKA:      I will accept that as another

19   friendly amendment.    Thank you.

20               DR. KASS:      I have Alfonso next.

21               DR.    GOMEZ-LOBO:      I'm    afraid   that     I   am

22   going to disagree with Charles here, but he knows

23   that.   Going to Michael Sandel's point.            I would put

24   it in very simple terms.
                                                                  220

1                  Namely, if you go into a lab and you           have

2    an embryo in a dish there, and you would not be able

3    to tell whether it was created for research or for

4    reproductive purposes.       There is nothing in the being

5    itself.

6                  And what I am trying to do is this, is

7    turn the discussion back to what I think is the key

8    point, namely what kind of being we are dealing with

9    here.      There   were   parts   of   the   paper   where   you,

10   Professor Outka, seemed to be treating embryos and

11   fetuses as if they were different entities.

12                 And I think at a given moment you would

13   talk about these entities and these other entities.

14   And it seems to me pretty common sensical that we are

15   talking about stages.       Every fetus was previously an

16   embryo, and an embryo developing naturally will become

17   a fetus.

18                 These are names that have been coined for

19   certain periods in the live of what, of a human being,

20   if we are talking about human embryos.           Just the fact

21   that we can talk about ovine embryos shows that the

22   world embryo doesn't tell us what sort of thing it is.

23   We need the word human there.

24                 Now, if that is the case, then of course

25   the big problem is if we have one human being, and you
                                                                    221

1    agree that from conception onwards that we have a

2    human being, then why this "diminution of value" in

3    one stage, and then from then onwards -- I don't know,

4    is there an increasing value?

5                  You   seem   to    take   implantation      as   the

6    breaking point, and I have heard that before.                    Of

7    course, you are familiar with the work of Tom Shannon,

8    I assume, right?     You quote him.

9                  DR. OUTKA:   I cite him in a footnote.

10                 DR. GOMEZ-LOBO:         Sure.    Sure.     Now, the

11   real    critical    question     is   this.        Are   Shannon's

12   arguments convincing?      Is it the case that there is

13   such a decisive break there that we may -- I think you

14   would   be   more   consistent    totally     to   disregard   the

15   value of the embryo, or to say, well, it is part of a

16   human being, and therefore it is equally valuable as

17   that same human being at a different point.

18                 Now, I don't know if we want to get into

19   the discussion of potentiality in the individuation.

20   But those would be the key points it seems to me,

21   because if a human being starts its conception, if we

22   have there the basic genetic information that is going

23   to carry this organism through the phase in which we

24   find ourselves, then of course I see no reason to
                                                                           222

1    think that there might be less value at that point

2    than at another point.

3                   In a way, it seems to me that people like

4    Robertson are a lot more consistent at times, and say,

5    well, let's respect -- or Mary Ann Warren for that

6    matter, but let's respect them after they are three

7    years   old,   after     they   are   rationale,        or    something

8    along those lines.

9                   So the point that I am trying to focus in

10   is why or on what grounds establish this magic break

11   point at 14 days?

12                  DR.     OUTKA:       Well,    thank      you   for     that

13   question.      I actually think your characterization of

14   the    position   --    well,   I    would       want   to    offer   the

15   following amendments to it, but then let me talk about

16   whether I think I have given anything like adequate

17   arguments for the positions that I take.

18                  But the great or the only bright light

19   that    I   see   in     this   range       of     possibilities        is

20   conception.       So, conception is the point at which

21   someone becomes a kind of primordial part of the human

22   race, and an embryo has the genetic wherewithal to

23   become a person just like the rest of us given the

24   right opportunities.
                                                                         223

1                   So    conception     is     the   first       and    the

2    brightest line for me.          Implantation is none of the

3    other subsequent discriminations that I also defend

4    are     anything     more     approximate,       but        they    are

5    approximate.

6                   So I don't actually make as much of the 14

7    day period as Shannon does.              I don't have this big

8    commitment to individuation versus the other.                    I stay

9    with conception.

10                  But I do say that there is approximate

11   discrimination at the point where implantation occurs,

12   because now we can describe this entity as a power

13   under way, a self-developing power under way.                       You

14   can't say that about the embryo.

15                  DR. GOMEZ-LOBO:      Why?

16                  DR. OUTKA:      Because it is not implanted.

17   It isn't yet a self-developing --

18                  DR.    GOMEZ-LOBO:          That's       a    circular

19   response.

20                  DR.   OUTKA:       No,    it's    not.        A     self-

21   developing power under way means that if left to its

22   own devices will, and if not interfered with, come to

23   term.
                                                                             224

1                  No embryo is going to do that prior to

2    implantation.        It       won't.     I     mean,    that      is    not

3    circular.    With respect, I don't think so.

4                  DR. GOMEZ-LOBO:           A fetus left to its own

5    devices won't survive either.

6                  DR. OUTKA:          In one way it will, in the

7    sense that it certainly depends upon the woman, and I

8    have tried to argue that the one person in all the

9    world for at least the first 20 weeks, and that makes

10   the circumstances of pregnancy sui generis in my view.

11                 It    is    a    satisfactory      analogy         that   are

12   entirely    satisfactory        elude    us.      But       nonetheless,

13   there is now a natural process where if the woman

14   doesn't do anything but live normally, that entity

15   will come to term.

16                 And that is not a generalization that you

17   can make about the embryo.             You can only make it about

18   the fetus.    So I do think that there is nonetheless a

19   difference.

20                 PROFESSOR MEILAENDER:              Leon, may I just

21   ask one question of Gene with respect to his response

22   to Alfonso.        Given what you have said, why did you

23   accept Charles Krauthammer's             comment       as    a   friendly

24   amendment since you have just -- it seems to me --

25   committed yourself to a very high estimate of the
                                                                225

1    embryo, if not from conception, at least from the time

2    of implantation?

3                 DR. OUTKA:    Well, then it is no longer an

4    embryo.   It is a fetus.    There is a --

5                 PROFESSOR      MEILAENDER:          Well,     his

6    distinction was at birth, and that was the friendly

7    amendment that you --

8                 DR. OUTKA:    Well, I know that it was, but

9    the embryo, though it has irreducible value, I want to

10   argue still -- that until it becomes a fetus, it has

11   moral standing, but not the same moral standing that a

12   fetus has.

13                DR.   KASS:     By   fetus,   you   mean    simply

14   implanted?

15                DR. OUTKA:    I mean implanted.     So there is

16   a irreducible value, but not the same kind of moral

17   standing that a fetus has.        I try to lay this out.

18   Whereas, equally protectable value, only occurs when

19   it is viable.

20                DR. KASS:     Could I intrude myself in this

21   just because I think that we spent most of the time

22   here on the nothing is lost point, and the distinction

23   between using the spare and creating for.

24                But it seems to me, and I am intuiting

25   from the silence of some of our colleagues, whose
                                                                               226

1    manner of making a living I am aware of and you are

2    not, but that we might like some help from you on

3    something else in this paper, which actually has to do

4    with the question of the evaluation of the status of

5    the    pre-implantation           embryo,    which      is    after       all

6    central to our business, whether we are talking about

7    cloning for biomedical research, or down the road to

8    embryonic stem cells.

9                   So central to your -- I mean, I think if I

10   understood the paper, you make a lot out of -- the

11   reason that you do not regard either abortion or the

12   destruction of embryos as murder, though you regard

13   the    embryonic      life   as    having    irreducible,         but     not

14   necessarily,        therefore,      equal    value       if   I     am    not

15   misunderstanding.

16                  And      that       turns     on     some      notion        of

17   potentiality, which you develop richly, and there are

18   people in this room from previous discussion who have

19   used    the    term    embracing       it,    and       others      use     it

20   dismissively.

21                  You would, I think, make a contribution to

22   our ongoing discussion if you could say a little bit

23   more about that notion, and to do it in a way in which

24   it     might   be     persuasive,      and        not   to    the        moral
                                                                         227

1    theologians   in    the   room,      but   to    those   of   us    who

2    studied some science.

3                  Can you help?           How does the notion of

4    potentiality, how does it help us think about this

5    thing that we have before us created in vitro if it is

6    not a full person, which if I understand your paper,

7    you don't claim that it is?

8                  That seems to be the core of your teaching

9    to us about its value, and if we don't understand

10   that, I think we may miss this.            So can you help?

11                 DR.     OUTKA:      Well,    I    can   try,    but   I'm

12   afraid that I will probably reiterate what is already

13   on the pages.       But maybe to refresh our memories, I

14   say that potentiality applies to embryos and fetuses.

15                 And I take fetuses first, and I say that

16   potentiality refers to what they are not yet, and also

17   what they are.        And I try to keep fairly low flying

18   here, in terms of trying to offer a descriptively

19   accurate characterization of them.

20                 They are not yet an equally protectable

21   life   because   by    virtue   of    this      dependence    on    one

22   person in all the world, and I do make quite a bit of

23   this, and that pregnancy does have this very special

24   feature.
                                                                     228

1                    Only the woman can help in a certain way.

2    She is strictly non-transferable.               There is no one

3    else in the world that can help if she doesn't.                 Now,

4    in a way that is a natural fact about us, but it is

5    also a very peculiar natural fact, though it is very

6    common.

7                    It is kind of numerically common and yet

8    it is striking in that there aren't precise analogies

9    to it.     And I want to argue then that during this

10   early    period    she    is   allowed    special   discretion    by

11   virtue of this absolute dependence that one entity in

12   the universe has on her, and only her.

13                   But potentiality also refers to what the

14   fetus already is, and what the fetus already is, is

15   this    power     under    way,   which     I   realize   has    not

16   convinced all of you of its accuracy.

17                   But      nonetheless      the   fetus     is    very

18   connected to the woman, and still totally dependent

19   upon it, but nonetheless again if she lives a normal

20   life, there is a self-developing quality to the fetus,

21   which if simply left alone will result finally in an

22   entity just like the rest of us.

23                   That is also a natural fact about it, and

24   it is this peculiar combination of what the fetus is
                                                                                  229

1    not yet, and yet is, that represents its peculiar

2    status in the world.

3                     And so I want to say that to kill it

4    causes    it     incomprehensible          harm,    and      that       is   what

5    makes    abortion and         infanticide so            serious,        because

6    there is nothing that we can ever do to compensate, or

7    make amends for that action to the entity.

8                     But I also then want to argue that embryos

9    are like fetuses with respect to having this reducible

10   value.     They have the genetic wherewithal, but they

11   are not yet a power under way.

12                    Now,    I    take    it that       given       the overall

13   assignment that you all have as a council, you want to

14   see whether or not, and especially your scientific

15   colleagues,         or   members      of    the     council         have     any

16   reactions      to    that     with    respect      to     its     scientific

17   adequacy, because that is part of your assignment, is

18   to get clearer on that.

19                    So I would ask any of you who care to, to

20   comment     on      whether    you     think       that      is     a    useful

21   description,        or wildly        inaccurate,        or   somewhere         in

22   between.

23                    DR. KASS:         Does someone want to join on

24   that?     I mean, there are people still on the queue,

25   and I jumped slightly.               The question of potentiality
                                                                230

1    came up here, and I know that it would be a shame if

2    you left without our having a chance to address that,

3    because it seems to be part of the case for the moral

4    work that we had here.      Paul.

5                  DR. MCHUGH:     Well, just a moment on your

6    question of potentiality.       I want again to underline

7    something that the professor said.       He said that this

8    has the potential if left alone.

9                  Well, that of course doesn't apply to, for

10   example,    the   human   development   from    somatic   cell

11   nuclear transplant.       You have to do even more to it

12   than just produce it to get it to be human.

13                 And I just wanted to make the point that

14   sometimes    potentials     depend   upon      further    human

15   actions.    And the council knows why I am fussing about

16   this, but I want to be sure that I heard you correctly

17   when you said the potential here is if left alone,

18   this entity will follow a course with --

19                 DR. OUTKA:    Well, you are perfectly right,

20   but that applies to fetuses.

21                 DR. MCHUGH:    Yes.

22                 DR. OUTKA:    It does not apply to embryos.

23   I mean, that is the difference between the two as far

24   as I can see.     If you don't do something in addition
                                                                     231

1    to an embryo, i.e., implant it, it will never be a

2    power under way.

3                    DR. KASS:    Bill Hurlbut, and then -- well,

4    are you going to speak to this particular point about

5    the science?

6                    DR. HURLBUT:       Yes.       The first thing is

7    that I think we need to come to the point of using the

8    same   terms.      Scientifically      speaking,    at    least    in

9    current literature, the term embryo is used for the

10   first eight weeks of development.

11                   But I sense that you are using it pre-

12   implantation and then --

13                   DR. OUTKA:     Yes, I am.       But I think that

14   has almost become in a way a de facto use.                  Do you

15   have a sense of that as well?

16                   DR. HURLBUT:     They are not using a term --

17   people are using a term, and Elizabeth suggested that

18   we   use   this   in   various    contexts,      pre-implantation

19   embryo,    or   pre-embryo,      but   that    actually   has     its

20   historical derivation from the term pre-implantation

21   embryo.

22                   And scientifically speaking, an embryo is

23   from conception until 8 weeks.                 There has been a

24   little fuzzing over the history of it.             But basically

25   the distinction that is trying to be put in place
                                                                         232

1    there scientifically is that approximately 8 to 10

2    weeks the organization is set, and it is not just

3    getting bigger after that, but it is much more like

4    that.

5                    The     early        development       of    form   and

6    organization are taking place.                One little scientific

7    comment and then I want to ask you a question.                            I

8    personally don't understand why you feel that in a

9    natural setting at least the pre-implantation embryo

10   has     a   different    moral       status    than    the   implanted

11   embryo.

12                   The     fact    is    that    the     pre-implantation

13   embryo is drawing nourishment from its mother, and as

14   is evident from the varied result that you get from

15   putting it into a different medium for a while --

16   larger offspring, for example, and more twinning, or

17   example.

18                   And so I can't quite see why that really

19   makes a difference.        But that might be the wrong point

20   to address.      What I would really like to know -- and

21   this is a very vexing question to me.                   I have sat in

22   this council now for -- this is the third meeting, and

23   every meeting the issue of potential versus actual,

24   and accrued, or accumulated status keeps coming up.
                                                                                233

1                     And I feel the good intentions of those

2    who bring it up, and I got in a little discussion with

3    Mike Gazzaniga about this the first week.                        I felt the

4    weight of it when Janet Rowley said it several times.

5                     I keep wanting to know, and wanting to ask

6    of     other     people     why     they     assign        a     particular

7    characteristic         of   accrual    as    being        the    moment      of

8    implicit dignity; and why the various sides of this

9    equation can't find some meeting point.

10                    So    I    would     really       like     --    I     would

11   personally very much value an exchange between you and

12   somebody at least on this panel, or on this council,

13   who is taking a position of accumulated or accrued

14   personhood,       or   something      of    that    nature.           Do   you

15   understand what I am getting at?

16                    DR. OUTKA:       Well, I think so, but let's be

17   sure I do.        I mean, my position is -- well, I hope

18   nuanced, but it is hard to pin down, because I both

19   want    to     attribute    irreducible      value        to    any   entity

20   after    conception,        and   still     make    as     you    say      some

21   distinction between the embryo and the fetus.

22                    And I accept by the way your pervasion

23   that by embryo I mean pre-implantation entity, and

24   that's what I mean.          And if there is an acceptable way
                                                                    234

1    to refer to that and that makes for clarity, I would

2    happily accept it.

3                   And you may be right that the embryo is

4    dependent upon the woman, too, in a way that I ma not

5    fully doing justice to.         It is perhaps significant

6    that I am thinking of embryos as potentially in a

7    state of limbo by virtue of in vitro fertilization

8    clinics.

9                   I mean, that has made me more aware of

10   implantation as a kind of stage that is discrete in

11   some ways.      So I may be overdoing that.              You are

12   certainly    right    that   unless    we    are   talking   about

13   embryos     created   that   way,     or    conceived   that   way

14   rather, we are not talking about an entity that is not

15   also dependent like a fetus is on the woman.

16                  But now let's go to your basic concern,

17   and maybe you had better repeat that for me, because I

18   am not sure that I do have it clearly, and it is

19   clearly an important point to you and to some others,

20   and I want to promote whatever I can by way of clarity

21   about your ongoing discussions.

22                  DR. HURLBUT:    Well, I would really, really

23   like personally to hear a good deep discussion on the

24   issue of the moral significance of potential.
                                                                      235

1                   And I don't know if it is too much to ask

2    for    specifically    from   one     of   my   colleagues.       For

3    example, if Mike Gazzaniga would actually jump in here

4    and engage this, because a lot hinges on this subject.

5                   And a few of us are deeply enough trained

6    philosophically to know the real or the deep thoughts

7    on what this term so factual and potential actually

8    mean.

9                   DR. OUTKA:     Well, I don't think that even

10   the    philosophers,    however      deeply     trained     they are,

11   have come to any agreement.            This is why in a way I

12   felt    more   emboldened     just    to     say,   look,    whatever

13   position you take on this status of the embryo and the

14   fetus    are   going   to   have     major    implications     for     a

15   position that you take on stem cell research.

16                  But there is so much disagreement all the

17   way down the line, and yet those disagreements matter

18   so much, I am going to tell you what my own views are.

19                  Now, I don't defend them altogether, and

20   that goes back to something that came up earlier.

21   There is a booklet in which I talk about abortion,

22   where I defend them a bit more.

23                  But some of that defense is still to come,

24   but nonetheless I think I am clear now on the general
                                                                           236

1    lines of the argument, even though I haven't fully

2    justified all the parts of it.

3                  DR. KASS:      Let me say -- and because there

4    are people in the queue, and we are moving toward the

5    end of this session, I want to let the people who have

6    asked to speak, to give them a chance.

7                  Could I simply say that this question of

8    either absolute or prima facie, were tied to something

9    actual or potential, it is not going to go away.                       And

10   that we had better put it on the agenda for ourselves.

11                 Lots    of     people      had   a   stake       in    this

12   discussion, and I think Professor Outka has in fact,

13   if we revisited those 3 or 4 pages of the paper.                        He

14   has given us something to chew on, but I suggest that

15   we perhaps bracket it for now.

16                 I     just     wanted      to    highlight        it      as

17   important, and unless someone really wants to join in

18   on and solve this one, let me suggest that we take the

19   people who are waiting.

20                 And    let's    try   to    do   this   in   about        10

21   minutes, and then break.         I have Robby, Frank, Janet,

22   Michael, and Rebecca.          That is rather long for the

23   time   that   we   have,   but   let     me ask    for     a    certain

24   concision if I might.            Who was the first?                 Robby?

25   Please.
                                                            237

1                  PROFESSOR GEORGE:    Thanks, Leon.   Well, I

2    will then lay aside the discussion and I was going to

3    go right into the questions that Bill and Alfonso

4    raised, but let me lay those aside right now, because

5    I have another set of questions that will take us back

6    to Michael's original comment and the exchange with

7    Gene.

8                  And perhaps I will write to Gene with my

9    own two cents about this question about the status of

10   the embryo.    But back to the set of distinctions that

11   Michael was calling into question, Michael Sandel.

12                 I take it that our position is that once

13   there exists an embryo, who will not be implanted, and

14   whose life will soon end one way or another, then it

15   is either -- and you can tell me which, and I don't

16   know whether it matters.

17                 It is either not instrumentalization to

18   disaggregate the embryo for good reasons, or if it is

19   an   instrumentalization,     it   is   not   a    wrongful

20   instrumentalization.

21                 I don't think you have declared yourself

22   on that, and I don't think that much turns on it, but

23   do you want to say which way you will look at it?

24                 DR. OUTKA:    it is probably closer to it.

25   I think that is a fine question, and I haven't really
                                                                       238

1    thought about it, but I think it is probably closer to

2    not a problematical instrumentalization.             I think that

3    is probably what I would say.

4                  PROFESSOR GEORGE:        Okay.    I take it then,

5    if I were going to try to defend a position given that

6    point against my point, I wonder if you would accept

7    this way of defending it.

8                  I have to confess in the end that I don't

9    think it can be defended, but I am just trying to see

10   how   far   it      can    be    defended    against        Michael's

11   particular critique.

12                 Then I think you would have to say that

13   the morally bad thing is in -- and I am sorry to use

14   this language, but I think it is in the spirit of what

15   you have been saying.           I am not going to talk about

16   motivation.

17                 But    the    morally    bad   thing     is    in   the

18   intention to create the embryo as an object.                 That is

19   to say, to create the embryo as a means only.                Is that

20   right?

21                 DR. OUTKA:        Yes.

22                 PROFESSOR GEORGE:        So that in way you have

23   distinguished creation by whatever means, and Michael

24   has to be right that the means don't matter, but the

25   creation of the embryo for reproductive purposes from
                                                                               239

1    the creation of the embryo again by whatever means for

2    research that would involve its destruction.                              Yes?

3    Okay.

4                    PROFESSOR GEORGE:            Then I think what has

5    to be defended to make that out would be the idea that

6    embryos created for purposes of reproduction are not

7    created as means or objects, but are created as ends

8    in   themselves,       even    if    we    know      that   some    of    the

9    embryos       that    are     created      will      in     fact    not     be

10   implanted,      and   therefore       will      be     subject     to   licit

11   disaggregation.        Right?

12                   DR. OUTKA:          Yes.     That is okay.              Licit

13   disaggregation is probably all right, but note the

14   somber quality of this, of accepting all of this.

15   This is mournful stuff.             I mean, I mean I am not happy

16   about it.

17                   PROFESSOR GEORGE:           No, I understand.

18                   DR. OUTKA:          It is not licit in a kind of

19   pure moral sense at all.                  It is like we have this

20   aftermath, and what do we do with it.

21                   PROFESSOR GEORGE:            That it is permissible

22   and that is the key.                We may be unhappy about the

23   whole thing, and regret how it came about.                              Okay.

24   Then    the    question       becomes     can     we    distinguish       the

25   treatment of the spares created, again by whatever
                                                                            240

1    method, in such a way as to make sense of the idea

2    that   despite      the     fact    that    they    are   going   to     be

3    discarded,       and        therefore      subjected      licitly        to

4    disaggregation as ins in themselves.

5                   And how does that argument go?                Does that

6    argument have something to do with the idea that each

7    has a chance of being the one implanted?                  Does it have

8    to be an equal chance, and that gets us into Jim

9    Wilson's problem about embryo screening?

10                  DR. OUTKA:           I don't think I have fully

11   worked out what I want to say about that.                  In part, it

12   is because I see the moral calculations that I am

13   trying to defend as working in response to decisions

14   made   by   others,         which   I    don't     necessarily    either

15   rejoice     over,      or    even       approve,    but   where   I      am

16   nonetheless forced to now deal with them.

17                  And what it is maybe licit to do to them.

18   I mean, there the status of fetal cadavers would be a

19   sort of -- well, the use of fetuses terminated in

20   abortion decisions would have a similar kind of status

21   for me, where I am deliberating about things where I

22   am not wholly happy about this data, but I am going to

23   have to now confront it and make some determinations

24   with respect to it.
                                                                  241

1                  And I am trying to offer a moral case for

2    doing that.     But I think that sometimes the force of

3    some of these questions implies that one is more of an

4    actor with respect to what is being decided about than

5    one is.

6                  And I would want to be wary about that,

7    and I think the way that you put that almost hints at

8    that, and I would want to resist it.

9                  PROFESSOR GEORGE:        Oh, I am willing to

10   grant you that, but it seems to me that then on the

11   other side, by the same terms, we have got Michael's

12   scientist.

13                 You know, he was not involved in any of

14   this, and he is just facing a batch, or at least one

15   embryo that is now in the condition that objectively

16   from   your   vantage   point    renders   it   legitimate   for

17   disaggregation.

18                 And he is willing to do it and doesn't see

19   any moral reason not to, because it seems to pass the

20   test that you set out.

21                 DR. OUTKA:        I said that there were gray

22   areas.

23                 DR. KASS:    Let me just remind you of the -

24   - I mean, I would still like to get other people on

25   the queue, and so if you could --
                                                                  242

1                  PROFESSOR GEORGE:        I'm sorry, I will --

2                  DR. KASS:    Well, I mean, could we ask the

3    following?    This sounds like a nice dialectic.            Would

4    you be willing to put in writing, and Gene, would you

5    be willing to respond, and we share this exchange?

6                  PROFESSOR GEORGE:        I would be intending to

7    write to Gene about the status of the embryo issue

8    anyway, and we can --

9                  DR. OUTKA:         That's excellent, but these

10   are very important questions.

11                 PROFESSOR GEORGE:        Just a final point on

12   where we would go and why I think it is relevant.                  I

13   mean, I am just wondering if at the end of the day

14   what   you   have   got   left    to   say   to   Michael   as     a

15   scientist is really a practical or prudential matter;

16   that simply if you go ahead and experiment or use it

17   to disaggregate these embryos, you will be encouraging

18   other people to do.

19                 DR. OUTKA:    I am not sure -- I am going to

20   try to assimilate Michael's scientist's case into the

21   general case that I want to make about the appropriate

22   use of discarded embryos.         That is what I am going to

23   do with it.
                                                                           243

1                     I am not going to allow it some kind of

2    independent status that derails the basic distinction

3    that I want to         make.

4                     DR. KASS:       Frank.

5                     PROFESSOR FUKUYAMA:              Well, I apologize,

6    but I am going to have to leave as soon as you respond

7    to my question, as I have one last class to teach this

8    afternoon.

9                     DR.    OUTKA:      I     won't    misinterpret     your

10   departure then.

11                    PROFESSOR FUKUYAMA:            This is in a way a

12   devil's advocate kind of question.                 But I am struck in

13   these discussions of bioethics often that you begin

14   with a moral rule or principle, and then as we have

15   done,     have    a     very     subtle     discussion      about     the

16   application of it.

17                    But there is no prior agreement on that

18   principle, and the one here is the Kantian distinction

19   between a means and ends, which we have all been -- I

20   mean, nobody has questioned that basic framework.

21                    Now, I personally would much prefer that

22   you be a Kantian than a utilitarian, and so I am not

23   hostile    to    Kantianism,       but     it   has   got   a   lot     of

24   problems.
                                                                          244

1                  I mean, for one thing, pure Kantianism

2    presupposes    a   dualistic       ontology    that     I    think     no

3    natural scientist sitting around this table would be

4    willing to accept.

5                  I mean, noumena do not obey the laws of

6    physics.     You know, laws of natural causation.                 But I

7    think also Kantian ethics is a big mess, because if is

8    ethics of intentionality.

9                  I mean, I don't really see under Kantian

10   ethics how you can fight a "just" war.                  I mean, when

11   Douglas MacArthur was a division commander in France,

12   he once said I will give a thousand men to take that

13   hill.

14                 I     mean,      if      that      is         not      pure

15   instrumentalization, and every military commander that

16   has ever lived has had to make a decision like that,

17   and if that is not instrumentalization, I don't know

18   what is.

19                 And this came up -- I think Mike Gazzaniga

20   brought    this    question    up    in   kind    of     our      e-mail

21   discussion    prior   to    this    meeting,     that       making   the

22   distinction between treating human beings as means and

23   ends just begs a lot of questions as to where you make

24   that distinction.
                                                                   245

1                   I have heard, for example, people argue

2    that since Kant believed that the noumenal quality had

3    to do with our ability to reason that it is actually

4    only fully adult human beings that deserve that kind

5    of protection.

6                   Which   means     actually      that   you    could

7    experiment on infants, and a lot of other people by

8    those rules.     So I just would like to hear you defend

9    why we should start from a Kantian premise rather than

10   some other kind of premise.

11                  DR. OUTKA:      Well, I mean, my reasons are

12   actually much lower flying than you might fear.                For

13   one, it did come up in the literature that I was

14   reviewing.

15                  Doerflinger mentioned it.          In his case,

16   and in mine, too, there is a kind of Christian -- but

17   I think you could have some more generally religious.

18   I think you could have some specifically Jewish or

19   other kinds of formulations, too.

20                  So it is set in a larger framework, and

21   that   is   point   one.    It   was   handy    because     it had

22   already been cited, and I was desperate to try to find

23   some ways to tie into what I had already presented for

24   reasons of space.
                                                                246

1                   But I don't think that it commits.                I

2    don't want to be committed to Kantianism, per se.                I

3    want to be committed to the second formulation of the

4    categorical imperative is one potentially felicitous

5    way to identify some things we should continue to care

6    about.

7                   But I will sort of reserve the right to

8    interpret it in my own ways, and also stress its

9    importance for our purposes only with reference to

10   illuminating    this,   the    problematical   character     of

11   doing something to X in order to, or with Leon's

12   friendly amendment, and as part of our plan to create

13   in order to destroy, or some variant of that.

14                  That seems to me to be objectionable, and

15   this was one way to try to make that point.          So low

16   flying acceptance, your cautions are very well taken.

17                  DR. KASS:      Very briefly, Janet, and then

18   Rebecca.

19                  DR. ROWLEY:     Actually, one of these is a

20   response to Jim Wilson, who unfortunately has stepped

21   out.     But I think it is not correct to say that the

22   mother to be walks in and looks at a petri dish and

23   says that I want that egg, and that one, and not the

24   others.
                                                                          247

1                 My     impression     is     that   is     not    how     it

2    happens, and there is no way at the present time for

3    us   to   suggest    or    to    screen    for       hair   color      or

4    intelligence, or any other features.

5                 We can screen for sex, and we can screen

6    for known genetic abnormalities that might actually be

7    relevant based on family history.                The other issue

8    that keeps coming up again is we are preserving these

9    eggs in perpetuity.

10                And     for    me   perpetuity      is    hundreds      and

11   thousands of years, and I think that is not what the

12   IVF embryos -- their fate and future is.                One question

13   that I personally am sorry that I didn't get a chance

14   to talk to, or ask to John Gearhart, is how long can

15   you really keep frozen embryos and expect them to be

16   viable when you thaw them out.

17                Now, I suspect it is some number of years,

18   but I don't know precisely if these embryos are kept

19   in liquid nitrogen, which is very expensive, and you

20   have to keep replenishing it in the tanks at major

21   costs to someone or some institution.

22                It is also clear that he said that at

23   least in his experience that one does look at the

24   embryos   that      are    developing     as     a    result    of         a
                                                              248

1    particular in vitro fertilization for a family, and

2    selects those that appear to be the best.

3                 And he didn't define exactly best, but

4    presumably either are growing somewhat larger, or have

5    more cells, or whatever features are used.

6                 And the leftover ones are not as good, and

7    that they have a much lower efficiency or viability

8    than do the ones that are selected for implantation.

9                 So I think for us to say that every single

10   embryo left over from IVF has the potential to go on

11   and develop into a robust embryo fetus and child is

12   probably totally incorrect.

13                And I think that we ought to be a little

14   more careful in how we frame some of these things,

15   because I think we are not taking into account some of

16   the other issues.

17                DR. OUTKA:    If you all ever find out that

18   question about perpetuity, and how long that actually

19   is, I would be very pleased to know.

20                DR. ROWLEY:    Well, what do you think, Liz?

21                PROFESSOR     BLACKBURN:        Well,    enzyme

22   solutions,   which   are   much,   much   more   biologically

23   simple than -- not only cells, but blastocysts, or

24   stages around them, and enzyme solutions will go "off"
                                                                                249

1    as you store then for a couple of years, even with

2    care and liquid nitrogen.

3                  So there must be some sort of half-life,

4    and so it is maybe a few years.             I honestly don't know

5    from IVF clients how that is going to be an assist,

6    but   just    based    on      the    precedent            of     even     less

7    biologically delicate material, I would be surprised

8    if it was more than a few years.

9                  DR.     OUTKA:         That   is       a    very     important

10   question.     The United Kingdom, I think, discards them

11   more decisively doesn't it?

12                 PROFESSOR        BLACKBURN:                 My      accent     is

13   Australian.

14                 DR. OUTKA:        Sorry.

15                 DR. KASS:        It is no longer that united.

16                 PROFESSOR BLACKBURN:               I am jumping ahead

17   to your inference.       I don't know.               I don't know what

18   the policy is.        So I am just speaking from my very

19   direct laboratory experience of delicate biological

20   material, which is much less delicate than these.

21                 DR. KASS:        Look, we need to break.                   I want

22   to give Rebecca the last word if I might.

23                 PROFESSOR     DRESSER:             I       didn't    try     very

24   hard, but I was trying to find out the answer to this

25   question, and I did see last year that there was a
                                                                           250

1    report of a healthy live birth from an embryo that was

2    stored -- I believe it was 9 years, and they presented

3    it as if this was the longest duration that they were

4    aware of.

5                      But obviously it is difficult on how you

6    do   the   research      to   find   out     the    answer.      I    was

7    interested in the fourth point that you mentioned at

8    the beginning, where you were going to focus on four

9    points,     and    the   fourth      point    was    this     issue     of

10   political and legal context.

11                     And you mentioned this issue of whether

12   there should be a different policy for private funding

13   and public funding.           And I know that is not really

14   your specialty, but I wondered if you had any thoughts

15   for us on that fourth point?

16                     DR.    OUTKA:         Well,       nothing      really

17   interestingly beyond what is on those pages.                   I mean,

18   I am distressed at the amount of liberality out there

19   in the private sector, where it really is just taken

20   as a matter of course that a thousand research flowers

21   may properly bloom out there.

22                     And I think that really is making too many

23   decisions by default, but that doesn't help us very

24   much.      And I did remark though that I think that a

25   number of people have come to the conclusion that if
                                                                 251

1    you try to impose some overall governmental criteria,

2    you are going to get conclusions that certain people

3    regard as too conservative and constraining.

4                  And so it is better to leave it alone, and

5    I am not myself prepared to just accept that without

6    further adieu.       But much more work would need to be

7    done on that.

8                  PROFESSOR DRESSER:      But you wouldn't take

9    the step that, well, that your position should be the

10   position that should be our public policy?

11                 DR. OUTKA:     No, I would not necessarily

12   presume to that, but I am a great admirer actually of

13   Canadian ways of managing their health care.              I just

14   have to confess that.

15                 And I do note in the last version of this

16   paper that the position I take is actually closer to

17   the recently announced Canadian one than it is either

18   to   the   more    restrictive   policies    that   the   United

19   States has, or the more liberal permissive policies

20   that the U.K. has.

21                 So    on   this,   or   on    Canada's   attitude

22   towards reproductive technology, and all of that, it

23   seems to me that they have been more responsible than

24   we have.
                                                                     252

1                    DR. KASS:     I want to thank Professor Outka

2    for an excellent paper, and for a very forthcoming and

3    lively discussion, and for all of you for actually

4    sitting patiently through what is a long and for many

5    of   us   an   intellectually      challenging   and    stretching

6    session.

7                    Thank you very much for being with us, and

8    we will take a break for 15 minutes, and then have our

9    last session.

10                   (Applause.)

11                   (Whereupon,     the   meeting    went    off    the

12   record for a break at 3:15 p.m.)

13                   DR. KASS:     Could we come to order?           Why

14   don't we begin?        I think a few of our members have had

15   to leave either for class or had a conflict for this

16   last session.      I think we're just missing Dan Foster

17   at the moment and maybe he -- ah, perfect.                     Good,

18   thank you.

19                   This is a session in which we return to

20   the topic of our last meeting and revisit our project

21   on cloning.       The specific questions are the ethical

22   issues of cloning for biomedical research and I would

23   simply remind us of the approach that we have adopted

24   in full recognition that not that we have failed to

25   reach     agreement,    but   we    never   expected    to     reach
                                                                     253

1    agreement    because   this     is   a   vexed,   moral   question

2    where   reasonable     people    put     the   moral   weight     in

3    different places, and that our effort is to explore

4    these differences with no expectations that they're

5    going to be overcome, but rather that they can be

6    clarified.

7                  The aspiration in this discussion and, if

8    you will, on this part of what we eventually produce,

9    a common document owned by us all in the sense that we

10   agree that this is, in fact, a good representation of

11   the state of the question, while preserving and even

12   sharpening our differences so that no position held by

13   any member of council or by some person not in council

14   that deserves to be represented in council isn't given

15   its fullest and fairest expression.

16                 We have been proceeding as colleagues, as

17   fallible human beings with a certain, I don't like the

18   term, but it's been used, with a certain kind of

19   epistemic modesty about our own claims, I mean, to

20   encounter thoughtful people who ought to know better

21   than not to agree with us, ought to give us somehow

22   pause and make us a little more humble about where we

23   stand and that we are interested, maybe when we leave

24   this room, we're interested in victory, but at least

25   for the sake of our meetings, we are adopting the
                                                        254

1    pretense we are interested in clarity and wisdom and

2    not simply beating the other side down.

3                I would suggest and so far, I think with

4    some perhaps exceptions, we have tried to recognize

5    that the people with whom we disagree have something

6    vital to defend and if I might be so bold, vital to

7    defend even for us whether we know it or not, and

8    therefore it behooves us to make sure that we don't

9    shortchange ourselves.    And one formulation would be

10   to say that it would be -- nobody would want to see us

11   callous to the needs of suffering humanity.      Nobody

12   would want to see us cavalier regarding the treatment

13   of nascent life at some stage or other and no one

14   ought to be indifferent to the effects on a society of

15   doing A rather than B, or B rather than A, or C or

16   none of the above.

17               So I want to tell you where I think we

18   stand in this discussion to see whether I'm right in

19   where we stand and then continue to have -- to advance

20   the discussion.    The question of the vexed status of

21   this entity, the cloned embryo, we're now back to the

22   cloning topic.    It's related, but not identical, with

23   the status of the embryo created by IVF, which will

24   be, I think, central to the question.
                                                                                  255

1                      I    want    to    remind    us    of    something        that

2    we've gotten from Stephen Carter in a message to us

3    about   the    importance            of   upholding       the    distinction

4    between what's legal and what's moral, between the

5    realm   of    what      is    permissible       legally         and    what    is

6    either good or bad, better or worse, noble or base,

7    right or wrong.

8                      All        too      often         and     perhaps           for

9    understandable reasons, the question of permission or

10   ban   hovers      over       the    moral     conversation,           but   it's

11   certainly possible that someone might conclude that

12   this activity is morally dubious, but ought to be

13   permitted      and          there     are     all     other       kinds        of

14   possibilities.          So I would like us, as best we can, to

15   have this conversation still on the moral plane which

16   is where we've had it before.

17                     I would also make an observation and this

18   has come also in some of the conversations, that some

19   of us have been adopting the language of competing

20   goods to describe the present situation before us.

21   And I would at least like to put before us that that

22   might   be    a       way    of     putting    the    question        that     is

23   congenial to some, but that there is another way of

24   formulating what's here and might help us understand

25   why this is so intractable.
                                                                 256

1                     In moral philosophy there is a distinction

2    made between the right and the good in which the good

3    is an object of desire.            There are multiple goods.

4    They don't have any kind of absolute standing for us

5    and you can compromise them to get more of one for the

6    sake of less of the other, whereas claims of right or

7    of justice are things which lay down a kind of marker

8    and at least there's a prima facie claim that they

9    should not be violated, that the burden of proof is on

10   someone to show why they should -- why they can't be

11   violated.        And I have the sense, at least in some of

12   the previous discussions, that for those people who

13   regard the embryo as either one amongst us or enough

14   like us to be entitled to some kind of irreducible

15   respect, that is not being treated as a category of a

16   good to be preserved, but as a matter of right.                 And

17   therefore, arguments of that sort are less likely to

18   -- people who hold that view are less likely to want

19   to put that into a pan balance of competing goods, but

20   who want to insist that this is one of those markers

21   like     "thou    shalt    not"   because    there's   something

22   inviolable here.

23                    I don't want to shape the discussion, but

24   I   at   least    want    to   introduce   that   distinction   as

25   possibly being helpful to us and seeing what might
                                                                     257

1    seem to be simply a matter if we talk long enough, we

2    can find the right balance, when in fact, for some

3    people this is not a balancing operation at all, but

4    two different kinds of moral discourse.

5                    I think that's -- there are other things

6    to be said, but I want to really open the discussion

7    with the following observation.             We have tried in

8    staff conversations and in conversations with you all

9    to stake out several moral positions with respect to

10   cloning for biomedical research and while two of them

11   seem to have come to the fore and have commanded at

12   least   some    support,   I    suspect   that    the    two   might

13   indeed be enlarged to four.         And let me state them and

14   see where we are.

15                   It   seems to    me there   are    two possible

16   grounds for approving or finding morally acceptable

17   cloning   for     biomedical     research   and    two    possible

18   grounds for disapproving.        One would be to approve and

19   to   let's     say   approve    with   eagerness    and    without

20   qualification because one does not believe that any

21   harm is being done.        This would be a view that held

22   that the embryo in question was beneath the status of

23   having any moral worth and I don't want to get into

24   the language of person and things.                 I'm not sure

25   that's helpful, but it is not the sort of thing that
                                                                         258

1    ought to restrain us from use when good might come of

2    it.     Let's call it the position of “approve with zeal”

3    or “approve without qualification.”

4                     The   second    would    be   to   recognize       that

5    there is something in the embryonic life here that one

6    is at least agnostic about it or one thinks it has

7    some kind of standing, but that one engages in a

8    balancing operation and it approves with humility and

9    is willing to accept some kind of restrictions or

10   restraint on what can be done, recognizes that there

11   is a harm being done to the embryo, but does not

12   regard    that     as a   moral    wrong, that       is   to   say, a

13   violation of some stricture of right.                This has been

14   put into a balancing operation.

15                    A parallel on the side of the disapprove,

16   it seems to me I'm going upwards in scale.                You'd have

17   a position that one could call disapprove with regret

18   or has been said, with tears.              I'm sorry, the tears

19   belong on the other side.                Approve with tears and

20   here,    disapprove but         with regret,    recognizing that

21   there might be certain kinds of benefits had, but

22   making     calculations     on     prudential       grounds    or     on

23   certain kinds of moral considerations about where this

24   might lead, that one decides, on balance, that the

25   goods    to   be    had   are    not   worth   the    cost     of   the
                                                                                 259

1    balancing operation. And there could be the position

2    that would disapprove as a matter of principle and

3    without qualification because it is immoral to treat

4    even the earliest of human embryos as anything but one

5    amongst us, no matter how much good might come from

6    it.

7                    I take it those are four positions that

8    have    been    heard    around      the    table,          not    necessarily

9    articulated      in     those       ways.         In    the       intermediate

10   conversations between the last meeting and this one,

11   we've been mostly working in the middle, that is to

12   say, we have -- I'm not exactly sure about that, but

13   we've    had     expressions         of     views       that       look    like

14   disapprove with regret and positions that argue for

15   approve,   but    with       humility       and    the      willingness       to

16   accept some kind of restraint.

17                   I think from some of the correspondence

18   that there are at least some amongst us who believe

19   that    their    view    of     this   matter          is   not    adequately

20   represented and I think it turns on the question of

21   whether we haven't made all too much fuss about these

22   little 7-day old embryos.

23                   Let     me    see    if I    have       correctly         stated

24   analytically where we are and if so, then the question

25   is where we can go to make sure that these viewpoints
                                                                 260

1    are properly developed before we actually either try

2    to persuade one another to move from where we now are

3    to some other place or we finally have to choose and

4    come down with what we really think about this.

5                   I think I've said both too much and too

6    little, but let that be -- to prime the state of our

7    own discussion.        I remind you, cloning for biomedical

8    research, the arguments of course overlap with the

9    question of the embryos used for research, but we're

10   back on our more narrow topic and the larger one is

11   still in the offing though perhaps informed by some of

12   the things we've just been talking about.

13                  Comments,         questions,          arguments,

14   corrections?

15                  Gil, please.

16                  PROFESSOR MEILAENDER:        Just very briefly,

17   I   just   want   to   note   that   it's   not   necessarily     a

18   question of whether someone thinks his or her position

19   has been kind of adequately represented in that focus

20   on the middle.         For instance, as I recall, one of

21   Frank Fukuyama's comments that he sent in was really

22   questioning whether the approve with humility position

23   was the right representation of the going argument in

24   a way and I, myself, had questioned whether it was

25   really the strongest form of the argument.              So it's
                                                                               261

1    not -- I think it's not just a question of whether one

2    thinks one's own position is represented, but just

3    where the balance of the argument should lie.

4                          DR. KASS:      Mike, do you want to get in on

5    this, please?

6                          DR. GAZZANIGA:         I'll take the bait.                I

7    think       we    should      do     everything     we    do   with      great

8    humility.         You realize how often in life you're wrong,

9    it's    a    good      model.        But    someone   with     I   guess my

10   particular         view      would    not    see    the   need     for    the

11   preceding two hours of torturous debate of trying to

12   shoehorn into this problem all of the issues that are

13   trying to be shoehorned into us.                    So I view the embryo

14   by which we mean the blastocyst, either formed by IVF

15   or through somatic nuclear cell transfer as a thing

16   that deserves human respect like all human tissue, but

17   provides         me    with    absolutely      no     moral    dilemma      to

18   proceed into biomedical research on it.

19                         DR.   KASS:      Does someone join           on    that?

20   This is, in fact, I suspect, a not uncommon position.

21   It might even be more common in this body than simply

22   Michael, so could we have some discussion?

23                         DR. GAZZANIGA:        I guess what I was -- I

24   don't know what other people think and it's up to them

25   to say.          But I do like what you've done here which is
                                                                            262

1    to broaden the spectrum of response to the question at

2    hand.

3                       DR. KASS:     Right.

4                       DR. GAZZANIGA:         And I think that was an

5    important gesture.

6                       DR. KASS:     Right.     Rebecca, please?

7                       PROFESSOR DRESSER:           This isn't exactly in

8    response to what you were saying, but in thinking and

9    reading about this, it seems to me that people in both

10   1    and    2     categories,     the     approval      categories     are

11   affected by some notion of duty to rescue or duty to

12   be   a     good    Samaritan     and     that    it's    not   just    some

13   judgment        about    the     value     of    the    embryo   or    the

14   viability of the embryo, but it's a moral -- a strong

15   moral feeling that this is what we ought to do to help

16   people who are very ill.               And I just wondered if that

17   is   a     concept      worthy    of     exploring      with   these   two

18   positions, that is, you know the moral philosophy on

19   duty to rescue and when do we have one and what are

20   the considerations that ought to go into determining

21   whether people have a duty not just to refrain from

22   harming, but to actually act to rescue people who are

23   in dire circumstances.            So I'll just throw that in.

24                      DR. KASS:      Let me add one further thing.

25   As you know from the start we have been trying to
                                                                           263

1    place     our   limited      moral    arguments       in   the      larger

2    context.        In    the    case     of   cloning     for    producing

3    children, we tried to put it in the context of human

4    procreation and with the help of some comments from

5    Michael    Sandel      and   others,       it's    clear     that   human

6    procreation also means relations between parents and

7    children.       It's not just the procreative act.                   We're

8    trying to put these things -- the right context for

9    this is not just what's the status of the embryo, but

10   the right context for this is what is the vocation of

11   healing     and      what    is,     in    fact,    the    mission      of

12   biomedical research and these are not simply technical

13   activities.          These are activities informed by deep

14   moral commitment and principles and the question is

15   whether these duties are absolute or relative and so

16   on is, of course, for discussion.                   But I think it's

17   absolutely welcome.           We can't simply hash this out

18   over the status of these 100 cells.                  We also have to

19   think really about the moral principles that guide us

20   here.   So that's, I think, very welcome.

21                   Elizabeth, please.

22                   PROFESSOR BLACKBURN:              I've been grappling

23   with this and I think that I'm in position 2, as

24   you've outlined it, approval, but thinking seriously

25   about it and for me a helpful metaphor was thinking
                                                                     264

1    about, well, if one were, let's say, there with a

2    blastocyst and you had to do something to keep it

3    alive and then you saw a child drowning, who would you

4    save, if it was a matter of you being in one or the

5    other place and you knew that if you went and helped

6    the child drowning, and I'm using a dramatic example,

7    but if you helped the child drowning, you would have

8    to let the blastocyst die because you couldn't carry

9    out whatever next thing you had to do to keep it

10   alive.     So to me, then the choice -- it very much

11   comes down to choosing between two things and making a

12   choice as to what is the more morally imperative, so

13   equating    research       with   its    goal   of   therapy   isn't

14   therapeutic benefit and other medical advantages to

15   the idea of saving an existing life in some way that

16   is a fully formed life.            So to me, it sort of came

17   down to an either/or.         Which one does one weight.          So

18   I think your category 2 seems to be fitted by that

19   metaphor.

20                  DR. KASS:      Please, Alfonso?

21                  DR. GOMEZ-LOBO:          I think that was a very

22   nice     illustration,       actually,      and      very   helpful,

23   although since both are duties of care, I don't think

24   that   there    is   any    really      serious   and   deep   moral

25   conflict.      I think that it's perfectly legitimate to
                                                                             265

1    care more for one than the other, if you can't save

2    both.     In fact, I would like to take up the -- perhaps

3    the challenge sketched by Rebecca and I think it's a

4    general way of clarifying things or trying to clarify

5    things.        I think we do have duties of care, moral

6    duties of care, duties to take action to preserve the

7    goods or to promote them and doubtless, our duties

8    involved in health care are usually of that nature.                           I

9    mean we make all sorts of effort to say bring our

10   child to the emergency room when the child is sick,

11   etcetera.         And    of       course,   that's     a    very,     very

12   important aspect of our moral life.

13                    On   the     other    hand,    we   have     duties      of

14   respect and we have duties not to harm.                    Physicians of

15   the older generation perhaps were quite familiar with

16   this, the "first, do no harm" principle.                         And now

17   these duties have to do with the impermissibility of

18   taking action intentionally that will deprive someone

19   of a good.        So in a way it's symmetrical with the

20   other    one    and     the   first    case    we    have    a   duty     to

21   promote,       protect        a    good,      otherwise       would       go

22   unprotected and that would make it a moral obligation.

23                    Now what happens when there's a conflict

24   between    the    two    because      that's    what   we're     talking

25   about.     If there were no conflict we wouldn't have
                                                                        266

1    much of a problem.           Now I don't -- I do agree that

2    some things we have duties of care, but duties of care

3    are usually not that dramatic because if something

4    goes wrong with one of the options, we're really not

5    100 percent responsible for it as in the case of

6    letting the blastocyst die.

7                  Now what happens when we have, I'm sorry,

8    did you want to interrupt?            Okay.     What happens when

9    we have a conflict of care and we have a conflict

10   between   care      and    respect?       If     I    understand     it

11   correctly, the tradition of moral philosophy tends to

12   say well, if the duty of respect is such that if you

13   act intentionally, you would be producing an important

14   harm to human good, then that should take precedence

15   over the care.

16                 Let    me     give   you an      example,     perhaps a

17   trivial one, but one which appears in ethics books

18   very often.      You have a bandit who has kidnapped 20

19   hostages, an American college woman goes by and this

20   man says look, if you kill one, I'll let the other 19

21   go and of course, that is perceived as a conflict

22   because of course this woman has a duty of care,

23   apparently,   to     save    19    people.      But    in   order    to

24   achieve   that      goal     she    has   to     harm,      that    is,

25   intentionally kill one person.                 Since that is the
                                                               267

1    primary action in which she is engaging, it follows

2    that the agent in this case should morally refuse to

3    do it.

4                   Now I'm sketching this argument because

5    for me --

6                   PROFESSOR SANDEL:      Excuse me, would you

7    say that even assuming that you know for sure that the

8    villain will kill the 19 of the 20 if you don't?

9                   DR. GOMEZ-LOBO:     Yes.    Well, first of all,

10   you never know for sure because there's another agent

11   making another decision there.            I mean we're not as

12   predictable.     Bandits are particularly unpredictable

13   and in most ethics books the bandit is called "Pedro".

14                  (Laughter.)

15                  That says something.

16                  PROFESSOR SANDEL:     The reason I asked is

17   if that condition did apply, then we would have the

18   nothing is lost principle to argue for killing the

19   one.

20                  DR.   GOMEZ-LOBO:     Sure.     Well, I   don't

21   subscribe to the nothing is lost principle by all

22   means.

23                  PROFESSOR SANDEL:    Nor do I.

24                  DR. GOMEZ-LOBO:     Don't sign me on on that

25   one.     Plus, I don't think there was a good application
                                                                           268

1    of the principle of double effect in our previous

2    discussion.        So I'm torn.        I'm definitely in group 3

3    here     because       from    the    marvelous       exposition      this

4    morning, I see that, well, we had heard that from Dr.

5    Weissman already.            I see how promising all of this is

6    and I see that there are these duties of care, but if

7    --   I   know   many of        you    will    not   concede       the "if"

8    clauses of the following sentences, but if embryos are

9    human beings at an early stage of the development, and

10   if we should not intentionally kill innocent human

11   beings, it follows for me that I should not violate

12   the harm principle in this case and that's why I'm on

13   level     3.       I    do    think    that    this    is     a    morally

14   impermissible action, but I regret it and that's why

15   my question is going to be whether the scientist can't

16   figure out a way of harvesting the stem cells without

17   doing harm and the reply, unfortunately, was no.

18                   DR. KASS:       Gil Meilaender and then Paul.

19                   PROFESSOR       MEILAENDER:          Well,    you're    in

20   charge.

21                   DR. KASS:        No, go ahead.        My rudeness and

22   his gentlemanliness give you the floor.

23                   PROFESSOR MEILAENDER:               Well, a couple of

24   things.        I just want to note with respect to the

25   example that Elizabeth gives, I mean I agree with what
                                                                         269

1    Alfonso says in the sense that it really brings us

2    back    to     your       comments   kicking     off    this    session.

3    Elizabeth's original way of formulating it was a way

4    of     thinking       about       several    goods,      clearly      in

5    competition since you could only save one.                     Alfonso's

6    way of reformulating it has to do with how he changed

7    it into the question of respect and care, but it's

8    really -- that's a form of the right and the good, in

9    a way.        And it's worth noting that there might be

10   other factors that would enter in.                I don't know what

11   you'd say to this, but even thinking of it just in

12   terms    of    the    competing      goods     model,    suppose    the

13   blastocyst is mine and the drowning child or whatever

14   it was, is somebody else's?              Does that count?        I mean

15   there are all sorts of factors that enter in here, in

16   fact.

17                   So the notion that we've only got one kind

18   of thing, namely stages of development that makes a

19   difference, when we weigh competing goods is not the

20   case, in fact.        It's considerably more complicated.

21                   We have obligations to try to do good as

22   much as we can, but that means within certain kinds of

23   limits and it means taking account of a whole range of

24   factors,      and    so    it's   just   worth    noting    that    it's

25   there.
                                                                       270

1                 Then the other thing I wanted to comment

2    on was just to come back to Michael's comment that

3    basically   what   he    was    saying     was    he    falls     into

4    category 1, as you outlined, that there's not really a

5    moral problem here, but that doesn't get us very far

6    to say that because we want to know then what will

7    give us a moral problem.        If the early embryo doesn't,

8    at what point would we have a moral problem and why?

9    In order to think about how persuaded we are by that,

10   we need some kind of characteristics or criteria or

11   something   that    will       help   us    think       about      it.

12   Otherwise, we only have a position and we don't yet

13   have a kind of a piece of reasoning that we can go to

14   work on.    We just need more to do something with it

15   there.

16                DR.   KASS:         Michael     has       in   previous

17   meetings, in fact, in the very first meeting if I'm

18   not   misremembering,     articulated      what    might     be    the

19   criteria for moral standing and they were pretty much

20   neurological, but I wouldn't speak for him.                 Could we

21   draw you out on this because it would be welcome.

22                DR. GAZZANIGA:       Sure.     One hates to try to

23   answer impossible       questions, but      you    can certainly

24   take approximations.       And the approximation that is

25   safe for all concerned who are concerned about your
                                                                          271

1    question is that by 14 days the British line in the

2    sand, we're dealing with a system that is brainless

3    and has no capacity for sentience.                    The brain cells

4    aren't even born and that's pretty raw, elementary

5    biology to -- for me to draw the line at the 14th day

6    and     then     people     come        back   and    give    you        the

7    potentiality argument and I also said something about

8    that which -- so yes, I'm willing to draw for -- where

9    are we, 2002, that a 14-day line in the sand is a

10   pretty       comfortable,       keeps    you   free    from   thornier

11   issues and I'm going to let someone else draw the next

12   line.

13                    DR. KASS:       I'm sorry?

14                    DR. GAZZANIGA:          I'm going to let someone

15   else draw the next line.

16                    PROFESSOR MEILAENDER:          Can we have 20 days

17   maybe?

18                    DR. KRAUTHAMMER:          Michael, could I pursue

19   that?        Michael, I just want to ask you, forget about

20   the legal issue here.            At what point, clearly, you're

21   not     at     all    morally     disturbed     by     working      on     a

22   blastocyst.          At what point in the development of this

23   entity are you personally morally disturbed?

24                    DR. GAZZANIGA:          Well, you know, let's see

25   how she goes.          One step at a time.           What's before us
                                                                    272

1    in terms of what the scientists are saying we can

2    provide     untold   remedies,    hopefully      they    can     be

3    provided.     For the time being, they would be happy and

4    everybody    would   be   happy   with    the   line   that    I've

5    drawn.    The line that I've drawn -- a line.           So in 10,

6    15, 20 years, if they come back to the meeting and say

7    look, we need to move that line, how much -- how good

8    their argument is, what people think about it is for

9    another time to be considered.           I don't think we have

10   to think that far into the future. I think can we make

11   a comfortable decision in 2002 and I think we can.

12                  DR. KRAUTHAMMER:      But clearly, what you

13   think about when this organism deserves some respect

14   has to have some influence on your thinking on this, I

15   would assume that you believe a newborn child deserves

16   protection.

17                  DR. GAZZANIGA:     Of course.

18                  DR. KRAUTHAMMER:      And I understand that

19   what you're saying of the 7-day-old blastocyst is just

20   a piece of tissue, clearly there's a point at which if

21   you were asked to do the research on this organism,

22   you would say no, and I'm just curious to know what

23   that -- you certainly have thought about this.

24                  DR. GAZZANIGA:      Well, I don't know if I

25   have.
                                                                        273

1                    DR. KRAUTHAMMER:           Perhaps you could give

2    it a try.

3                    DR. GAZZANIGA:          I mean the obvious, from

4    the neurologic base, the obvious fact on the ground is

5    that    the    organ   that      is   responsible    for   everything

6    going     on   in   this     room     is   the   brain.     And    the

7    discussions of the issues of human dignity, of human

8    concern, piety, sympathies, those are all constructs

9    of the human mind and so that means you need a brain

10   around to enable those concepts to be used.                    So one

11   could say that you at least needed the presence of a

12   nervous    system      and   a   nervous    system   doesn't      start

13   forming for 4 or 5 weeks and that nervous system, as

14   you know, is impoverished, it's not ready to do the

15   kinds of things we're doing now.                 And then you start

16   getting into all these unanswerable questions and I

17   just would rather set those aside because I don't have

18   those problems at 14 days.

19                   DR. KASS:        Do you want to continue?

20   First of all, Michael is very good natured and he's

21   not shy, if I may speak for him.                  And I think that

22   this, if we're here, let's pursue this a little bit

23   further and see if we can get some clarity on this, if

24   people don't mind.           I'm taking advantage of your good

25   nature.
                                                                       274

1                      DR. GAZZANIGA:       We'll see how good natured

2    I remain.

3                      DR. ROWLEY:         Have you checked with his

4    wife?

5                      (Laughter.)

6                      DR. GAZZANIGA:        Sure, go ahead, push me,

7    push me.

8                      DR. KASS:    Did you want to go further?

9                      DR.   KRAUTHAMMER:       Well,   I   don't,   as      a

10   former psychiatrist, I'm guessing here, but I don't

11   think I'm going to succeed.              The position I've taken

12   which cut down a lot of trees to publish in The New

13   Republic this week, is based on basically a slippery

14   slope argument.         It begins by trying to not assume any

15   intrinsic worth to the 7-day blastocyst, but asking

16   were    we   to    pursue     this    research,    particularly      in

17   cloning where you create for the purpose of using the

18   blastocyst and destroying it, what will we become?                   So

19   I think it is relevant.              If you think that it becomes

20   wrong to do the research at a fairly near point after

21   that, and as I understand what you're saying, Michael,

22   it would be at the point where there's beginning of

23   neural development.           But you seem to also be saying

24   that you want to draw the line at two weeks, so the
                                                                    275

1    slope here, I don't know how slippery it is, but it

2    isn't a big slope between 1 week and 2 weeks.

3                   DR. GAZZANIGA:    This is where I am in over

4    my head.   I like to call up philosophers I know and

5    say can you help me with this slippery slope thing.

6                   (Laughter.)

7                   And they say oh, that's been written about

8    and there's a pro side and a con side.                And I say

9    okay.

10                  (Laughter.)

11                  I'll take the con side and we hang up.

12   You can get a driver's license when you're 16, right?

13   Now someone said well, what about 15 years, 11 months,

14   30 days, is that really different than 16?            Nah, it's

15   not   really   different.       Well,    about   15   years,     11

16   months, and 29 days.         Pretty soon with the slippery

17   slope argument you can get down to where babies could

18   be getting driver's license.            And of course, that's

19   nonsensical.     So what we develop as a species is a

20   capacity for form categories, categories of action,

21   what is generally acceptable.           And all I'm suggesting

22   is that we have a category here that we can make a

23   clear decision about and in that way get around the

24   slippery slope analogy which I think can find you in

25   some pretty slippery situations.
                                                                   276

1                   DR. KASS:     Bill?

2                   DR. HURLBUT:     Here's what it seems to me

3    to come down to.        Some people would say that what

4    you're talking about here is not a license to drive,

5    but a license to kill.           Now I'm not a lawyer and

6    unfortunately, as I look around the room, it seems to

7    me there aren't any left.

8                   Oh, good, right, okay.          Rebecca, you're

9    here.      But my understanding of the law concerning

10   abortion is that it was not fundamentally a right to

11   take a life.       That was a circumstantial secondary

12   effect.    The woman had a right of privacy to evacuate

13   her womb of this alien presence that was not, she did

14   not have an obligation to have.        Okay?     Maybe you can

15   correct me in a second, but let me keep going.              So now

16   we have -- you say we have this capacity to form

17   categories.    And I want to say parenthetically, I have

18   a lot of trouble figuring this out too, so I'm not

19   trying    to   attack   in    saying   this,    but   I'd     like

20   clarification on it.         You say we have this capacity

21   for categories.     Well, one of our major categories is

22   this distinction between a life present or in process

23   and its right to continue or whatever you want to call

24   it.     I don't even want to use the language of rights,
                                                                     277

1    but this is a major category, this position that you

2    should never take an innocent life in process.

3                   Now here's what troubles me about all this

4    from the slippery slope side of the argument.                   I'm

5    also troubled by the potential argument, but let's put

6    that one aside for the moment and here, Mike, I want

7    to ask you a specific question.

8                   So if you really go down and you talk to

9    people about stem cell technology as I've tried to do

10   and by amazing circumstances I know quite a few of the

11   major figures in this field, my assessment of it is,

12   yes, we might be able to find the reagents and bathe

13   the culture in them and get the proper cells we want,

14   but that in fact, we're more likely to get what we

15   want if we were to gestate it for a while, either in

16   utero    or   artificially     of    some   kind   of   ectogenesis

17   could be generated.

18                  So now what I want to ask you --

19                  PROFESSOR WILSON:            Mike, what was that?

20   What could be generated?        I didn't hear you.

21                  DR. KASS:        Growth outside, ectogenesis.

22   It grows outside the womb.

23                  DR. HURLBUT:         It turns out that a lot of

24   what    happens   in    the   development     process    is   highly

25   circumstantial.        So people working with stem cells are
                                                                          278

1    beginning   to    appreciate       how    there   are    these    other

2    little micro environments, that if surrounded in a

3    semicircle by one kind of cell which are sending a

4    diffusible agent in in a particular way, then another

5    agent    coming     from    the   other    side   will       cause   the

6    differentiation, but you can't just bathe it in the

7    reagents.

8                  The point is that it seems more logical to

9    me   that   you   reasonably       could    produce     more     useful

10   therapeutic tissues by allowing gestation or some kind

11   of artificial gestation to go for a while.

12                 So I want to take the opposition position

13   for a moment and say why not go beyond 14 days and why

14   restrict ourselves to 14 days now if brain criteria --

15   I think even now my assessment is we could learn a lot

16   and progress faster with the science if we didn't draw

17   that    boundary.      So    I    really   feel   as    though       that

18   boundary is really just shifting the question of not

19   taking an innocent life to 14 days instead of point of

20   origin.

21                 DR. GAZZANIGA:         Are you in a position 1,

22   we're haggling price here?

23                 DR.     HURLBUT:       No,    because      I    said    I'm

24   prescinding from the question of potential for the
                                                                          279

1    moment.      So just on your principles, I want to know

2    why we would draw the line at 14 days.               And why now?

3                    DR. GAZZANIGA:           I just told you.     It is a

4    line that is comfortable for me to draw.                  It is a line

5    that would allow the research to go forward.                  I won't

6    keep repeating myself.

7                    DR. HURLBUT:         But you said a minute ago

8    that you are comfortable with the fact that until

9    there's a neurologic system which you said was 4 to 5

10   weeks, that you didn't think there was any increased

11   moral standing, so why would you not set that boundary

12   for   the    moment   at   4   to    5    weeks   which    would   make

13   science progress much faster.

14                   DR. GAZZANIGA:            I don't know enough to

15   know whether you're right or wrong.               I leave it to the

16   adjudicating     regulatory         panels   might   inform     us     on

17   that.       I don't see this as a crucial point whether

18   it's 14 days or whatever.                 I'm comfortable with 14

19   days and I'm simply stating my position of 14 days.

20                   DR. HURLBUT:        I'd also like to comment on

21   -- I'm sorry Mary Ann is not here.                 Her summation of

22   the last which is relevant here that she seems to be

23   moving towards a conservative position on this issue

24   because of the failure of -- to see any demonstrable
                                                                              280

1    products or line of research that are coming out of

2    various stem cell efforts.

3                    DR. GAZZANIGA: There's a wonderful article

4    in    Science      a    couple      of     weeks    ago    entitled     "Some

5    History Should be Repeated."                       And they review the

6    claims and concerns of people about the recombinant

7    DNA research in 1976 where there was a group of people

8    from Cambridge, Massachusetts where a lot of this was

9    going to go on at MIT that felt funny little organisms

10   were going to ooze out of the MIT labs and envelop

11   Cambridge     and       people      were     going    to    die    of   these

12   horrible things, yadda, yadda, yadda.

13                   And in a similar meeting held in 1970, the

14   late 1970s, they set up this regulatory agency and as

15   a    result   of       now   going       ahead     with   recombinant    DNA

16   research, none of which was immediately envisioned at

17   the time, we now have, according to this article, 11

18   major   drugs      that      are    used     in    diabetes,      hepatitis,

19   acute    myocardial          infarction,          rheumatoid      arthritis,

20   stroke serving and saving the lives of millions and

21   millions of people.

22                   So the notion that I think some people not

23   scientifically trained don't quite understand is that

24   let the scientists                 roll.     They'll figure it out.
                                                                        281

1    They'll    figure       it    out     and      they're    the      most

2    conservative people in this room.

3                     DR. GAZZANIGA:      They beat each other up on

4    a daily basis as to whether what they're saying is

5    correct or wrong.            But you can't project into the

6    future    what    they'll    find    out.       You   have    to   just

7    understand       the   competencies     that    they're      currently

8    arguing for and then let them go to work.

9                     DR. KASS:    Dan.

10                    DR. FOSTER:    I just want to interrupt for

11   one second.

12                    DR. KASS:    Please.

13                    DR. FOSTER:        I want to say something a

14   little bit later, but I want to respond to Bill in one

15   sense.     We, ourselves, as a council, tend to have

16   different views.        We can sort of sense what, as Leon

17   said, and he's come a long way to try to get us into

18   thinking about these things.            I think it's critically

19   important in terms of, as Charles would say, building

20   a fence, that we not try to expand what has already

21   been done already when           -- outside.          I think it's

22   critically important.           I myself would be perfectly

23   happy to draw the line at the blastocyst level because

24   I think all the initial basic science can be worked

25   out there and to start moving beyond to the 20 days
                                                                                  282

1    and so forth.            Maybe that would speed up the science.

2    I don't know about that at all.                     We may find something

3    from the blastocyst in terms of mutation rates and all

4    sorts of things, going to pass away.

5                       My own view is I'm starting to get -- but

6    I    think    it    would      just    be        crazy   from    a     practical

7    standpoint to try to say the council wants to come up

8    and extend what we can't even agree on here ourselves.

9    So    that's       not    a    moral        --    the    only     reason       I'm

10   hesitating to say this, it's not a moral issue, but

11   sooner   or    later,         we    have    to     get   off     of    the high

12   standards of moral things and talk about practical

13   things as well.           I think we're starting to talk about

14   very practical things this afternoon.                      I maybe want to

15   come back to that a little bit, my comments about that

16   a little bit later, but I sure would -- Gil, I always

17   learn things from what you say and write and send me,

18   but I think this time, you're wrong.                            I think it's

19   wrong    to        try    to       expand        this    thing        out,   both

20   practically and in terms of trying to get a consensus

21   on some views, our views here in the council.

22                      DR.     KASS:           Let     me    say     I     think       I

23   understand.          I don't want to pretend to have mind

24   reading capacities.                 But I've been in a number of

25   these discussions and I begin to get to know who's
                                                                283

1    talking.     I      think    what's    at   issue    in    this

2    conversation, let me see if I've got it right.            Mike

3    Gazzaniga   sees     no     moral   difficulty   with     using

4    blastocysts because he does not regard them as being

5    things of moral worth.

6                He     was    asked   by several people to     say

7    well, all right, and he also enunciates a powerful

8    moral principle for going forward, namely, we're going

9    to learn good things and important things and people

10   will benefit from it.

11               So no harm, and great good.             What's the

12   problem?

13               Then people want to know well, is there a

14   place where you would have a problem so that if we

15   want to join you we want to know where this train is

16   going and where the limits are which is partly why

17   Charles wants to know, why Gil first of all wants to

18   know what's the ground of this, where is there going

19   to be moral standing and then he gives the argument of

20   nervous system and then the question is well, is the

21   14 days merely a prudential calculation because that's

22   all we need right now and he's willing 15 years down

23   the road to go some place else.        I think that's what,

24   in effect, Michael was saying.         But there are people

25   who are nervous and who want to hear the principled
                                                                                 284

1    defense because what they hear here is something like

2    the    duty     to    care    and      cure    being    treated       as       an

3    unqualified imperative beneath which everything else

4    has to submit. And so part of the question for those

5    of us who would care about something, about not doing

6    harm     or   not     violating        that    which    should        not      be

7    violated, they want to know is there a place.

8                     Now    other    people        have    used    the     14-day

9    marker not as a merely time saving place for the time

10   being,    but    who     really        think    that    14     days       is      a

11   transitional point, whether it be implantation -- I

12   don't mean by that just transfer into the woman, but

13   actual    physical       implantation          into   the     wall    of       the

14   uterus where you actually have the beginning of a

15   pregnancy, until that time, you don't -- or who want

16   to talk about the primitive streak or who want to talk

17   about the absence of twinning and who try to provide

18   some   kind     of     biological      foundation       for    saying          ah,

19   there's something here now not fully one of us, but

20   that's a biologically-based boundary, not in a nervous

21   system, but something else that might count for the

22   discussion.

23                    So     for     some     of     the    people        in        the

24   conversation who want to know, is there something in

25   the nature of things that would give us a guide if the
                                                                             285

1    blastocyst is not it yet?                 I think that's part of the

2    conversation.

3                   And the other part of the conversation

4    seems to be to test out what actually is the limit of

5    the moral imperative on the side of going forward or

6    are we simply going to say there are sick people out

7    there who need these things and until you come to

8    newborn infants, which I think was the implication of

9    Charles' question, it's ultimately fair game because

10   we can't really, I think, and this is not my -- this

11   was an attempt to summarize what I thought was going

12   on in the conversation.              I would add a position of my

13   own.    Yes, we are faced with a certain practical

14   decision here and now, but we have to think about the

15   meaning of the kinds of decisions we take here and now

16   for what it legitimates in the future.                          Yeah, and

17   therefore,     we    should         try    and   find     a    good    moral

18   foundation as well as being prudential and practically

19   sensible here in trying to reach this and to see

20   whether we can find a place to rest our head, if we

21   can.    If not, I think we're in danger of reaching an

22   unprincipled        kind       of   compromise         which   offers     no

23   guidance to those who are going to come after and who

24   might look to this body which was invited to think

25   about   this   with        a    view      to   where    this    is    going,
                                                             286

1    admittedly   with uncertain    knowledge, but    with some

2    power to predict some of the things that might be

3    coming ahead.

4                 DR. FOSTER:     Leon, I always seem to start

5    these long speeches that I was not speaking to the

6    issue that you posed before us about the moral things.

7    I was talking about a very practical thing and I

8    didn't want to divert off into some other thing.              I

9    want to get back to this.      I was not making any moral

10   argument at all.   I think it's perfectly legitimate to

11   do that.     So if you were lecturing me, I was not

12   attempting to make a moral argument.

13                DR. KASS:     Excuse me, it wasn't a lecture

14   to you.

15                DR. FOSTER:    Well, it sounded like it.

16                DR. KASS:     No, sorry, Dan.   It was heading

17   off what I thought were going to be people pouncing on

18   you.

19                DR. FOSTER:     I'm so delighted that you're

20   going to take care of me just like the fetus, you have

21   to take care of me, right?     Okay, I'm just kidding.

22                DR. HURLBUT:    Can I respond, Leon, just to

23   that because I have a very salient point to respond to

24   that.

25                DR. KASS:   Okay.
                                                                           287

1                  DR. HURLBUT:         And it ties to what you're

2    saying.

3                  DR. KASS:      Okay.

4                  DR.   HURLBUT:         Dan,    we    were    told    this

5    morning    that   fetal     primordial      neural    cells      may    be

6    useful in Parkinson's disease, right?              Okay.

7                  DR. FOSTER:      Some people believe that.

8                  DR. HURLBUT:         But let's assume it's right

9    for the moment.        Now it's not abstract and it's not

10   way off in the future.             It's here and now.            So why

11   then would we say, on what principle will we say that

12   a person should not clone himself, gestate or hire

13   somebody or gestate for themselves the embryo up to

14   the age to harvest out those particular very useful

15   cells?     This is right here, right now.              And yet, the

16   question -- and look, let me make two other points.                         I

17   am a physician.        I really want to see the science go

18   forward very, very, very much.              I feel the weight of

19   this.     I dream it actually, but I think if we define

20   our   principles,      we   will    allow    the     science     to     go

21   forward because then we will, for example, if we say,

22   full,     generative     potential     is    not     acceptable         to

23   violate, then we've got the possibility of creating

24   partial     generative      potential,      perhaps,       and    going

25   around it, the moral problem in a moral way.
                                                                 288

1                 If we define our larger principles well,

2    it will allow the science to go forward.             Otherwise,

3    it's going to get stuck in this morass of conflict.

4    So what I see myself as saying here is something

5    positive to try and set the future in an open way.

6                 Moral reality is a fragile reality in any

7    given society and it's something we have to contend

8    with. We can't just ignore it.        I think it's harder to

9    set a moral tone of cooperation in a society than it

10   is to make scientific progress.         But hopefully, they

11   can go forward together.

12                DR. KASS:       Paul McHugh.     Thanks for your

13   patience, Paul.

14                DR. McHUGH:       Well, I'm going to distract

15   us, I think, from that kind of conversation, but only

16   to reiterate what has been and to emphasize what has

17   been the subject of the conversation between you and

18   me in our epistolary debate in the e-mails.

19                I feel that we will totally submerge into

20   arguments of opinion over actions if we don't agree or

21   come to hear that the somatic cell nuclear transfer

22   clonote is different than the zygote.         With Michael, I

23   can partially agree that the clonote should have -- be

24   the subject of study because I think of it as an

25   artifact   and   I   think   it   different   from   a   zygote.
                                                                         289

1    Where I disagree with Michael is that dealing with a

2    zygotic natural program is equally okay.                    In fact, I

3    wanted to make a point about Mary Ann Glendon.                            I

4    think she would say her argument was not conservative,

5    but liberal in the sense of wanting to encompass more

6    people under the umbrella of our protection, but the

7    issue of the science here in what we're talking about

8    is an effort to bring science forward in the best way.

9                     I want to emphasize what I said in those

10   notes,     that    is,      that    the     lived      experience     of

11   scientists making somatic cell nuclear transplants is

12   not that they are creating a new individual, that they

13   are then going to destroy.                They are thinking that

14   they     are    producing    tissue       that   has    a   particular

15   program and that they're going to use that tissue at

16   some     time    for   the    benefit      of    everyone     and   I'm

17   approving of that and I want to support that.                         In

18   fact, I do support it.             I believe that the artifact

19   can then be misused if brought on into reproductive

20   cloning, but the fact of it as a different kind of

21   thing permits different kinds of actions towards it.

22                    DR. KASS:     Do you want to answer publicly

23   one question on this?

24                    DR. McHUGH:       Yes.
                                                                    290

1                 DR. KASS:       You believe that the clonote is

2    an artifact different in kind because it's different

3    in origin from a zygote, correct?

4                 DR. McHUGH:       Different in its origins and

5    in its constitution.

6                 DR. KASS:       And in its constitution.          And

7    should that cloned -- should that become cloned at the

8    blastocyst   stage    and    should   it    be   implanted     for

9    reproductive purposes and should a child emerge, would

10   that be a human child or would that be an artifact?

11                DR. McHUGH:        Well, first of all, those

12   actions should not be done.

13                DR. KASS:       But --

14                DR. McHUGH:       That human person would be a

15   different person, although you would extend to him

16   because he was tragically created, natural rights to

17   him, but you would see him as a person mistreated and

18   never to have been created.

19                DR.     KASS:      But   not   a    member   of   our

20   species?

21                DR. McHUGH:        Not quite a member of our

22   species in the same way, yeah.

23                DR. KASS:       Even if capable of reproducing

24   with another member of our species to produce more

25   members of our species?
                                                                       291

1                       DR. McHUGH:    He would be different.

2                       DR. KRAUTHAMMER:     Is Dolly not a sheep?

3                       DR. McHUGH:    Dolly is a sick sheep.

4                       DR. KRAUTHAMMER:     But Dolly is --

5                       DR. McHUGH:      But this would be a sick

6    person and we would have to take care of him.

7                       DR. KRAUTHAMMER:      But Dolly is a sheep,

8    sick or not, she's a sheep.              I think she's a sheep,

9    right?

10                      DR. KASS:     The question has been joined.

11   I don't know if we can sort it out.

12                      DR. McHUGH:     The point of saying that the

13   clonote      has     these     potentials,    that    if   they    are

14   illegally and I would believe that this would be as

15   illegal as slavery or as genocide, that because it has

16   those potentials, that therefore it should be treated

17   as though only those potentials characterize it or

18   that it should be conceived of as only characterized

19   by potential would be an error, an error of logic and

20   an   error    that     would    hold   back   the    advancement    of

21   science.

22                      DR. KASS:     Instead of arguing, let me see

23   if I can put you on the map of positions, the moral

24   positions on this question so we know what homework we

25   have to do.
                                                                292

1                 If I now understand you, you do not regard

2    cloning for biomedical research to be a moral problem

3    because the thing that is produced isn't on the human

4    moral scale and therefore --

5                 DR. McHUGH:         I found it problematic to

6    take your spectrum because I was looking at where I

7    would place myself.

8                 DR. KASS:     You're in a fifth position.

9                 DR. McHUGH:        To some extent I hold myself

10   in the place where -- between 1 and 2, okay?            I don't

11   think any harm is being done by creating a clonote. I

12   think   something   good   is    being   done   by   creating    a

13   clonote.   But because it is a special kind of new, a

14   kind of biology, I would therefore not permit it to be

15   implanted in a uterus, so maybe therefore I'm treating

16   -- approving with humility in some way because I'm

17   putting limits around what I would do with it.

18                DR. KASS:     Okay.

19                DR. McHUGH:         You see, if you take the

20   point that the clonote is something different, it's

21   something manufactured rather than begotten, then you

22   would want to study, use its best potentials for human

23   kind and not let its potentials for error and slavery

24   appear, okay?

25                DR. KASS:     I owe you a 5-page e-mail.
                                                                            293

1                    DR. McHUGH:         Yes.

2                    DR. KASS:       You'll get it.       Dan, please?

3                    DR. FOSTER:         I don't want any e-mail.                 I

4    never write e-mails in these things and the one that I

5    sent   I    said      don't    circulate.          I'd    rather   talk

6    personally, but that's okay.

7                    Let me make a preliminary remark.                  Leon

8    said a moment ago in passing, he used a phrase that I

9    think Adam Seligman popularized called epistemological

10   modesty that in the philosophy of studying knowledge

11   that you looked at limits and so forth.                         I think

12   epistemological modesty means that you believe certain

13   things, but you're modest about these claims and you

14   can be a believer and yet say I'm not really sure.

15   And that's sort of a fundamental fault line here in

16   the discussion.

17                   I take seriously and I've been influenced

18   by the people who occupy position 3 here and I'm not

19   willing    to   agree       with    Paul   that    this    is   just     an

20   artifact.       I think there's serious issues here that

21   make me nervous.

22                   But    if     you   live   in     what    Alfred   Shutz

23   called paramount reality, that is being wide awake in

24   the every day world, that's what paramount reality is,

25   it seems to me that common sense shows that a 100-cell
                                                                                  294

1    human       embryo    with     a    potential         to   ultimately,         if

2    everything goes right, becomes a human, has to be

3    taken as serious, as being serious.                        But it seems to

4    me from this wide awake view that it's different and

5    it doesn't have the same demands for protection and

6    respect as let's say something a little bit later.

7    But I don't know that for sure.                        And that's why I

8    think one has to occupy what I think I and what I know

9    I occupy which will be position 2.

10                      It seems -- I don't -- I'm not comfortable

11   with Rebecca's view that there's some messianic demand

12   to rescue people.            I think there are great virtues in

13   suffering and death that come to humanity.                           I think

14   none of the things that are great in humanity would

15   occur without threat and suffering in the world.                               If

16   there were not pain, there wouldn't be any need for

17   mercy.       If there were not fearful things, there would

18   be no room for courage.                   One could go through the

19   whole litany of what makes humans different and great

20   or    the    consequences          of   risk    and    suffering        in   the

21   world.       That does not mean that when we're given these

22   brains      that     we    should       not   try   to     make   the    world

23   better.       I'm distressed enormously by the fact that

24   the    slope    of        evolution      in    science     appears      to     be

25   steadily upward and that the slope of evolution for
                                                                        295

1    human    kindness    and    beneficence      and     morality    seems

2    almost not to have moved at all.

3                   And      therefore,     I        think    there's     an

4    obligation for those of us who live in this world and

5    want it to be better to try to make wherever we can

6    the world better and if you take -- I may be the only

7    one in the room that really actively takes care of

8    patients and --

9                   DR. McHUGH:      Hold on.

10                  DR.    FOSTER:        I'm    sorry,      Paul.      He's

11   retired, but he still takes care of them.                        Okay,

12   forgive me for that.

13                  But it is a daunting thing to deal with

14   death.    I just lost my long-term colleague.              We did 30

15   years    of   science    together.         We    did    good    science

16   together and from a glioblastoma multi-form and there

17   are papers, somebody read the PNAS paper last year

18   where you can mark, you can put human glioblastomas in

19   and then just infuse adult neural stem cells in the

20   peripheral blood targets, the glioblastoma, you can

21   take the mass out, but they infiltrate, you can just

22   see pictures.        There are two new articles in Nature

23   and   Medicine   just      showing   them       infiltrating.       But

24   these adult cells clamp on to them and you modified

25   them so that you can give a small drug and convert it
                                                                 296

1    into a chemotherapeutic agent across the blood-brain

2    barrier.       I mean we tried to see if we could do

3    anything for humans like that.

4                   So   myself,   for    myself,   it's   perfectly

5    clear that we ought to try to do better in terms of

6    medicine and the relief of suffering and I don't think

7    the   worry,    although   I'm    very   worried   about   it   is

8    sufficient to stop that.

9                   Here's another point that I think I made

10   --

11                  DR. McHUGH:    Can I ask you a question then

12   about that, Dan?

13                  DR. FOSTER:    yes.

14                  DR. McHUGH:       Can I ask you would you take

15   a blastocyst that was naturally formed, taking it out

16   of a uterus, a natural blastocyst and use it in the

17   way you want to use the clonote?

18                  DR. FOSTER:    No.

19                  DR. McHUGH:    Why wouldn't you?

20                  DR. FOSTER:       Because then I would clearly

21   be interrupting a progression, unless nature took it

22   away.

23                  DR. McHUGH:    Well --

24                  DR. FOSTER:    Let me answer it another way.

25   Everybody talks about if you use this, you're going to
                                                                      297

1    destroy it.     Well, I don't know what the figure is,

2    but 30 to 70 percent of the embryos that form normally

3    are deleted by nature.         So what do we say that God is

4    destroying these --

5                   DR. McHUGH:      Would you put a filter in a

6    uterus and pick up those and then use them the way you

7    want?

8                   DR. FOSTER:     I would not.

9                   DR.   McHUGH:       I'm     coming    back   to     my

10   artifact which you wish to use as an artifact, but

11   deny.   That's what I'm saying here.

12                  DR. FOSTER:     Well, I guess --

13                  DR. McHUGH:      You are saying that things

14   which occur naturally you wouldn't use, but things

15   which come out by cloning you would use and I believe

16   that that's because you see an artifactual nature to

17   the clonote.

18                  DR. FOSTER:      Well, I don't think that's

19   what I believe --

20                  DR.   McHUGH:       Well,     would   you    use        a

21   naturally occurring blastocyst formed --

22                  DR. FOSTER:      You mean while it's in the

23   uterus?

24                  DR. McHUGH:     Yes, when it falls out of the

25   uterus.
                                                                                298

1                       DR. FOSTER:          You mean if you take it out

2    of the uterus?

3                       DR. McHUGH:         yes.

4                       DR. FOSTER:         No, I wouldn't.        I don't want

5    to get into --

6                       PROFESSOR SANDEL:             that's not the only

7    possibility.

8                       DR.   McHUGH:          No,    that's      not   the   only

9    possibility.

10                      DR. FOSTER:         I don't want to get into one

11   of these long e-mail exchanges that you and Leon try

12   to do.        I'm just trying to make a simple, succinct

13   point and then I'm going to stop right here in just a

14   second, but I do think that we -- that I feel a strong

15   obligation not to stop this and the only thing I was

16   going to say and I argued this with Charles a moment

17   ago, I think if we allowed this to go forward, that is

18   biomedical research, if it turns out that it doesn't

19   work, I agree with Mike, the scientists would be the

20   first    to    quit      and    so     will   biotechnology        companies

21   because if it doesn't work, if it's got mutations in

22   it we'll end it.             Or, if there are better ways to do

23   this    as    I    think       there    may     well   be,    it    will     be

24   abandoned         quickly.       We've        seen   that    all    over     in

25   medicine that we abandon things when they go through.
                                                                299

1    So my view is, let's try to learn from this and keep

2    it very limited and I'll pay the price of tears, if

3    that's what it is,     if it turns out that in some sense

4    that the universe thinks I've killed a child, which I

5    hope we get rid of that murdering and killing things.

6    I   mean   there's   some   sort   of   an   implication   that

7    scientists are unethical or immoral or less ethical or

8    less moral than people who are not scientists and I

9    want to try to get away from that.             But if that's

10   wrong, then I'll try to tell the universe sometime,

11   I'm sorry, I made a bad mistake.             But on the other

12   hand, in the meantime I want to try to see if we can't

13   help a whole lot of humanity with what to me seems to

14   be a different sort of moral problem than the idea of

15   beyond ending a life that's not neurons and other

16   organs and things of that sort.

17                 I didn't mean to talk so long.       I just was

18   really trying to say that I'm in the position of with

19   a lot of concern as to whether I'm right or not about

20   that.

21                 DR. KASS:     Charles?

22                 DR. KRAUTHAMMER:         I'm a 3 and I'm there

23   for prudential reasons.        Mike says and I think if I

24   have the quote correctly, those not trained in science
                                                                              300

1    don't   understand        that    what   we    need      to   do    is   let

2    science roll.

3                   Well,      we let     science       roll   in    the      20th

4    century.      We    got    eugenics.          We   got    the      Tuskegee

5    experiment.     We had such horrors in mid-century that

6    we needed the Nuremburg Code.              Humanity hadn't had to

7    write it before, but it had to write it after.                      So I'm

8    a   little    skeptical          about   letting         science      roll.

9    Scientists    are    one    of    the    great     resources        in   any

10   society.     They do the science, but they don't own the

11   science.     And the reason that we're here is because we

12   don't have a guild system in this society, we have a

13   democracy.     We don't say to auto makers you know how

14   to make cars, therefore you will determine what safety

15   standards will be in cars.               No, it's the nonexperts,

16   it's the lawyers and the Congress who decide what are

17   going to be the safety requirements in cars and that

18   is imposed on the experts who make the cars and that's

19   how we do it in a democracy and that's why we have

20   this council to advise the President and the country

21   on what restrictions might or might not be applied on

22   what is undoubtedly a wonderful enterprise.

23   But we don't have a guild system in which all the

24   rules are made internally, not in a democracy.
                                                                           301

1                     The reason I'm against research cloning is

2    not because of the reasons underlying position 4 which

3    is somehow attributing a worth to the blastocyst equal

4    or at least comparable to that of a human, but out of

5    a prudential consideration as to what happens if we

6    don't.

7                     The first slippery slope and I think an

8    argument that in and of itself would be enough for a

9    person to oppose research of cloning is that I think

10   there    can't     be    any    doubt   that    if   we    sanction     an

11   industry -- and it will become an industry -- for the

12   creation      of       cloned    embryos,       it    is     absolutely

13   inevitable that we will begin to see those embryos

14   implanted and we will have the moral horror of having

15   a cloned embryo in gestation which under penalty of

16   law would have to be destroyed and that is a moral

17   certainty that I think is intolerable. But as I wrote

18   in my piece in The New Republic, that is a little bit

19   too   easy.        I    think   it   would     be   reason   enough to

20   prudentially           oppose   research       cloning,      but   let's

21   assume, put it aside.           I think there are other reasons

22   and the reasons are that once you start on this, once

23   you start rolling along this road, it will lead us to

24   places where I think that we don't want to go.                     I may

25   be wrong, obviously nobody knows exactly how we will
                                                                  302

1    end up or where this will take us, but I think a

2    prudent society needs to make choices based on past

3    history and some understanding of human nature.

4                 The    problem,   Daniel,   is    not    that   the

5    research might fail.       The danger is that it might

6    succeed wonderfully and we will then have scientists

7    say as we just heard, give me three more weeks with

8    this embryo.    Why not have a fetus where the organs

9    are developed and use them for transplantation rather

10   than have a Rube Goldberg system of growing it into a

11   blastocyst, teasing out stem cells, tweaking them into

12   developing   into   cell   lines.     Why     not    let   nature

13   produce with that wonderful     machine a fetus and let's

14   strip it apart for its parts?        Most of us would say

15   today that is unconscionable.       Well, I suspect that if

16   we live in a society where we do this kind of stuff at

17   an earlier level, for a decade or two or three, it

18   will be less unconscionable.

19                In the end, I think the major issue here

20   is that we are crossing a new barrier with research

21   cloning and that is the creation of embryos solely for

22   their use and I'm afraid that once you do that and we

23   create an industry in which this will be the business

24   of that industry, embryo creation, that we will so

25   desensitize ourselves to the use or misuse of this
                                                                            303

1    entity that we will end up doing things that we don't

2    want to do and don't want a society to do.

3                       I think that prudential argument is one on

4    which       we    can     argue    about     well,     what     are    the

5    likelihoods of these things happening, but I think we

6    ought to be realistic, that once you start on that

7    road, we will be, as a society, far less able to

8    resist the temptations that today seem obvious that we

9    ought to resist, but tomorrow, probably won't.

10                      DR. KASS:      Jim Wilson?

11                      PROFESSOR WILSON:         I've listened for years

12   to    Charles      and    read    Charles    for    years     without,       I

13   think, disagreeing with a single word he's uttered

14   until today.             And my problem is with the slippery

15   slope argument.           The slippery slope argument which we

16   hear much of in the literature although it's rarely

17   defined, is kind of a warning sign that's put up on a

18   highway, don't go any further or unknown bad things

19   will happen to you.              But rarely is it carried out to

20   show that if you walk past that sign, these unknown,

21   soon-to-be-named bad things will, in fact, happen to

22   you.        The slippery slope argument here does have a

23   name as what's going to happen to us if we permit the

24   use    of    somatic      cell    transfer    for    the    purposes     of

25   creating         clones    for    biomedical       research.      It     is
                                                                            304

1    inevitable that we will soon have cloning to make

2    babies    and    perhaps        cloning    to    produce     from     fetal

3    organs parts to be used by human beings and after that

4    God knows, perhaps organs taken from babies.

5                     That's       an    argument     that    can     be    used

6    against every advance in medical science that has been

7    made that I can think of.                We must not invent surgery

8    because the use of the scalpel to take out an appendix

9    will inevitably, on the slippery slope, lead to organ

10   harvesting and the selling of kidneys and livers on

11   the public market.              We must not allow neurosurgery,

12   even to cure a terrible tumor because it will lead

13   inevitably to lobotomy.             Now, in fact, lobotomies have

14   occurred.         And    in     fact,    some    instances      of    organ

15   harvesting have occurred, but the public's horror and

16   the government's horror at these things has quickly

17   shut     down    those    enterprises          and    penalized,      often

18   severely,       the    people      who   did    it.     Or   perhaps     we

19   shouldn't       have     automobiles       because      we     will   have

20   fatalities.       Well, we do have fatalities, but then we

21   balance the value of the automobiles with the value of

22   the fatalities.          Or we shouldn't -- you can make an

23   argument about any human innovation and say we must

24   not adopt it because we'll be on the slippery slope

25   and it is, in fact, a Luddite argument, unless you're
                                                                   305

1    able     to   show   that   sliding    down   that    slope     is

2    inevitable.

3                    Now you might be able to say that sliding

4    down that slope is inevitable in the case of cloning

5    because there will be such a huge financial demand for

6    the benefits of cloning that any form of cloning,

7    however benign in original intention, will lead to the

8    worse forms of cloning to satisfy that demand.                But

9    from all the scientific testimony I've heard so far,

10   there isn't this huge financial demand and there isn't

11   because nobody has found yet the exact techniques that

12   competent, but ordinary physicians can use to cure

13   these diseases, so that I want us to back away from

14   the prudential or this particular prudential argument

15   because I don't think it's correct unless Charles is

16   in a position to show that the slope is so slippery,

17   so covered with banana oil, that one step past the

18   warning line we have now drawn on the pavement will

19   bring us down into chaos.

20                   DR. KRAUTHAMMER:      Well, let me give you a

21   recent    and   empirical   example    of   that   slope.     The

22   country had a debate on stem cells about a year ago

23   and the major argument by the proponents of stem cell

24   research -- and I was one of them -- was that we are

25   using discarded embryos, everybody understood that,
                                                                       306

1    and we were going to bring a benefit from something

2    that would otherwise bring no good.               The understanding

3    was, in fact, Senator Frist made the presentation on

4    the floor of the Senate and he established conditions

5    under which he would support stem cell research, the

6    regulations that we ought to institute in support of

7    that     research      and     among     them     he    listed    very

8    emphatically that the research would not be done with

9    embryos created for the purpose of using for stem

10   cells.    That was what he said.

11                    Now and here we are a year later and we're

12   arguing over a technique of cloning which can only be

13   done in a manner in which an embryo is created in

14   order to destroy.        So within a year, what we have is

15   the ground shifting on this debate on precisely a

16   point that a year ago we had been assured would be

17   excluded by regulation and by law.

18                    PROFESSOR     WILSON:          The    Senator   Frist

19   example     is     a    good     one,     a     particularly     good

20   illustration of the proposition that Congress doesn't

21   often mean what it says.          You could use an even better

22   example with the 1964 Civil Rights Act and Senator

23   Humphrey's assertion to the Senate at large that it

24   would never be used to establish quotas or goals.

25   These things do happen.            But the fact that a year
                                                                                 307

1    later, a year ago or two years ago, whenever Senator

2    Frist spoke, we now find ourselves discussing this

3    subject.        It's very different from saying that the

4    subject,      once     having       been          discussed         and     some

5    authorization        once    having      been      past,       we    have    now

6    slipped down the slope to the point where we are

7    creating      clones        for    the        making      of     babies      and

8    harvesting organs from fetuses.

9                     DR. KASS:        Janet, did you want to comment?

10   Please.

11                    DR.   ROWLEY:           Well,     let     me    first      just

12   respond    to    Charles      because         I   think    though     Senator

13   First   may     have   made       some    comments,        I'm      sure    that

14   anyone in the field of cloning and embryonic stem

15   cells would not have supported his point of view.                             So

16   it isn't as though we started and we're downslope.                                I

17   believe    that      individuals         in       embryonic         stem    cell

18   research had already envisioned that, so we haven't --

19   that position has not been changed of the people who

20   are involved in it.

21                    I would like to respond to the discussion

22   that Leon framed as we began this session and my

23   points of view are certainly influenced substantially

24   by my view that we are really, we have the potential

25   of being on the threshold of some major biological
                                                          308

1    discoveries that will be of enormous importance, but I

2    qualify that with the same statement I made when we

3    began this discussion in January, that this is a hope

4    and at the present time we have no idea as to how much

5    that hope will actually be successful and that was

6    reiterated and confirmed again by both speakers this

7    morning, that these are very, very, very early days

8    and the promise that many of us see in this kind of

9    research may -- I think it's not fair to say that the

10   promise will not be realized, but I think that it is

11   fair to say that the promise may take a very long

12   time.     And I just want to point out that we began the

13   war on cancer in 1970 with the notion that it was all

14   going to be over in 10 or 20 years and we're far from

15   it.     We're far from it because we're dealing with very

16   complex systems in cells about which we are woefully

17   ignorant, but I think the part of the research that

18   will be permitted by going ahead with cloning and some

19   of the aspects of experiments with somatic nuclear

20   cell transfer will enlighten us so much that we'll be

21   able to see better how to expand on these in the

22   future.    And I would only echo our morning speakers by

23   saying that I think that to ban this kind of research

24   which has the potential for therapy would be a great

25   tragedy.
                                                                            309

1                     DR. KASS:      Michael Sandel?

2                     PROFESSOR SANDEL:          I just wanted to pick

3    up on the last small uncharacteristic slip of Charles

4    where     he    slipped    back     into    the     polemical        action

5    description to use Professor Outka's phrase of what

6    cloning        for    biomedical       research     is.       I     thought

7    following       Paul's and      Leon's     corrective        which    Outka

8    accepted, we agreed that there are two possible action

9    descriptions for both of these practices.                     By both, I

10   mean creation of embryos for reproductive purposes and

11   creation of embryos for purposes of medical research,

12   a charitable description and an uncharitable one.                       The

13   charitable       description      in     each   case     describes      the

14   action in terms of the end it's aimed at.                         So in the

15   case of embryos created for reproduction we point by

16   the description to the end.               Likewise, in the case of

17   cloning for biomedical research, the end there is the

18   creation of an embryo for the sake of promoting the

19   curing     of        disease.     There     is      an       uncharitable

20   description available equally to both and if we want

21   to compare them, compare the moral status of these

22   practices,       we    should      use     either      the     charitable

23   descriptions of each or the uncharitable descriptions

24   of each.        The uncharitable descriptions in each case
                                                                         310

1    doesn't refer to the end being aimed at, but instead

2    to the foreseeable, though undesirable effect.

3                   So   it   would   be    fair    to    say    that    with

4    Charles and with Outka's paper that in the case of

5    creating an embryo for the sake of biomedical research

6    to describe that as creating an embryo in order to

7    destroy it, but only in the same sense that we should

8    describe creation of embryos for reproduction purposes

9    as the creation of embryos in order to discard the

10   inevitable extras that will accompany the practice of

11   IVF.   So   both     activities       admit    of    charitable     and

12   uncharitable    descriptions      and     if        we're   going     to

13   compare their moral status, we should compare them

14   either under one description, the things they aim at

15   or under the other description, the foreseeable, but

16   undesirable side effects that accompany both.

17                  DR. KRAUTHAMMER:         Michael, I'm surprised

18   that you also made an uncharacteristic slip when you

19   said the inevitable destruction of the embryos in IVF

20   because you know, as I know, we could, in principle,

21   establish an IVF clinic tomorrow in which you assign

22   only a single embryo to a woman.              So you would thereby

23   have a process of IVF where you have no inevitable,

24   indeed, indeed no discarded embryos.
                                                                            311

1                 On    the   other       hand,    in    cloning,      it     is

2    absolutely   inevitable       that    that embryo,         because       it

3    will be disassembled, will be destroyed.

4                 PROFESSOR SANDEL:           Well, if the practice

5    of creating embryos for reproductive purposes involved

6    no spares, no extras, then it would have a different

7    moral   status    and    character      from       the    practice       we

8    currently have.

9                 DR. KASS:        Elizabeth?

10                PROFESSOR         BLACKBURN:            It     would        be

11   different from natural which, in fact, if anything the

12   majority of embryos naturally are lost and destroyed -

13   -

14                DR. KRAUTHAMMER:            We'd be improving on

15   God.

16                PROFESSOR BLACKBURN:            That's good.

17                PROFESSOR SANDEL:           What the natural case

18   Elizabeth    raises      is     the     --     there's          also     an

19   uncharitable description of natural procreation which

20   would be very odd, which is you're engaging in the

21   inevitable   creation     of    spare    embryos         that   will     be

22   sacrificed for the sake of having one that works.

23                PROFESSOR BLACKBURN:            Well --

24                PROFESSOR SANDEL:               And there's no more

25   warrant for that description than for the contentious
                                                        312

1    version of the description in the cloning for medical

2    research case.

3                PROFESSOR BLACKBURN:    Well, I think it

4    might be helpful to return to somewhat more the homely

5    and something Gil said that he said to me, well, would

6    you say the blastocyst, if it were yours versus the

7    child and I think I wouldn't be able to look the

8    parents of the child in the face if I hadn't made an

9    attempt to save the child.     And I think that also

10   addresses the issue of should we be trying to do

11   cures, even though we know that they're not inevitably

12   going to work tomorrow, next year, 10 years or 20

13   years.   I think we have to try and so I think this

14   question of the fact that we don't have successful

15   answers right now for whether embryonic stem cells or

16   somatic cell nuclear cloning is going to work, I don't

17   think that absolves us from the necessity to try when

18   we see real human disease and suffering that we should

19   try to act on, even though we know we may not be

20   necessarily successful in every attempt.

21               DR. KASS:   Gil, and I then I think I would

22   like to put my oar in and I'll give rebuttals, but we

23   should probably wind up.     We need a nap before we

24   drink, right?

25               Gil, do you want to comment?
                                                                             313

1                       PROFESSOR MEILAENDER:          Well, just a couple

2    of   things    quickly.        To    pick    up    Elizabeth's      point

3    again.     The hypothesis was and I think it's worth

4    thinking about, the hypothesis was that you could only

5    save one of the two entities, so that I don't know how

6    we set up this case the way the philosophers do it,

7    but there's a fire and you can go up one stair to save

8    the newborn in the crib who's not yours or you can go

9    up the other stairs to save the blastocyst in vitro

10   that is yours.        Okay?

11                      DR. KASS:       That's a copy of your dead

12   child, if you want to make it --

13                      PROFESSOR MEILAENDER:          Whatever.      It's not

14   -- it's not immediately apparent, kind of, that one

15   choice must be made and that suggests that there are

16   other    considerations        and    it's    not       just    stage     of

17   development.         The other thing I just wanted to say in

18   response to what Michael -- just -- I mean Gene Outka

19   can sort of take care of himself, but as a matter of

20   interpretation, I think he didn't quite grant what you

21   described him as granting.              I think he granted that

22   creating      in     order    to    destroy       was   a      tendentious

23   description.        He did not grant that the two situations

24   were the same where he had recourse or double effect

25   line which because he did still think that in the
                                                                             314

1    description      of        the        one    act,    the    killing      was

2    inextricably involved and I take that's really what

3    Charles was getting at.                So it isn't in terms of what

4    he was granting, I want to be clear.

5                    DR. KASS:             Okay, I'm winding up to -- I

6    want to say a couple of substantive things, but come

7    to a procedural suggestion for what we should do next.

8    First, since Jim Wilson began by being surprised that

9    he could disagree with Charles, I'm surprised that I

10   have    to    disagree      with       Jim    Wilson   with      whom   I've

11   disagreed only once before and he since told me that

12   I've persuaded him, but I'm not going to do it again.

13                   PROFESSOR WILSON:              Not this time.

14                   DR. KASS:              The slippery slope, to call

15   something a slippery slope argument is already to put

16   it in a category where you can abstract it and then

17   say you like those arguments or you don't.                       Rather, it

18   seems to me, it's worth thinking about, not in general

19   in the light of other examples, but to think about it

20   in the context of the particular thing we are talking

21   about.

22                   I think I might have said once before that

23   the reason that arguments about continuity of action

24   are    so    appropriate         in    the    area   that   we    are   here

25   talking      about    is    because          development    is    itself      a
                                                                        315

1    continuum and the value of the thing being developed,

2    never mind morally, but biologically, increases with

3    development and if it should turn out that tissues

4    down   the    road    are    really     more    valuable    for    the

5    treatment     of    the   same   patients      we    now   want,    the

6    argument that's now being made for doing it will be

7    very hard to resist.

8                   The real essence of the slippery slope

9    argument is not a prediction, an empirical prediction.

10   It is a question of the logic of justification and

11   it's   very   important      how    you   somehow     justify      what

12   you're doing here because if, as in this area, the

13   continuity     of    development        and    the   continuity      of

14   research offers such great promise, you might, without

15   even knowing it, be countenancing the next sort of

16   stages and in the end you will wind up as Bertrand

17   Russell said about pragmatism.            It's like a warm bath.

18   It warms up so imperceptibly you don't know when to

19   scream.      Eventually, we will get to some place that

20   none of us would want to be and we therefore have to

21   be very careful.          It's not a prediction of a certain

22   kind of certainty, although we have seen, I mean five

23   years ago The Washington Post editorialized on this

24   question.      No    creation      of   embryos,     especially     for

25   research -- use these others.             The newspapers are no
                                                                         316

1    better than the Senators on this and times change and

2    there were no stem cells five years ago.                 The benefits

3    to be had were less.

4                  I     think   it's     very    important      that    we,

5    instead of calling this a slippery slope argument,

6    talk about the question of prudence and if we put it

7    in those terms, then the question is: Is it really

8    prudent to head down this road and I don't think you

9    have   to   believe    that    the   embryo     is   a    full     human

10   person, at least to be worried, not just about what's

11   -- the destruction question.                It may be a terrible

12   thing to say in public, but I worry much less about

13   the destruction of the embryos as I worry about the

14   exploitive    mentality       on   the   part   of   not    just    the

15   scientists, scientists are trying to do good, but of a

16   community    that     comes    to    accept     as   routine,       the

17   instrumentalization of nascent life and in which we

18   become sort of desensitized to this.                 This is not a

19   question about the ontological status of the embryo,

20   but about how we come to regard those earlier stages

21   of our own being. I don't know what they are, but that

22   they're somehow part of a continuity with what we are.

23   Of that, as a biologist and not as a religious figure,

24   I mean I see the continuity.
                                                                  317

1                   Two other things, just for your thought.

2    I don't want to harangue much longer.               The IVF case

3    has been around a number of times, but let me suggest

4    one thing.     The fact that there are a lot of embryos

5    lost   in    normal   sexual    procreation   doesn't     settle

6    anything.     It doesn't really settle anything.          And it

7    seems to me one could say something like this with

8    respect to that in the IVF clinics.         When a couple now

9    undertakes to procreate by ordinary sexual means, if

10   they've learned the facts about this, they know that

11   they are saying yes to the sad fact that there will be

12   a lot of loss.

13                  That's just the way things are and without

14   going Charles' route about improving God's way, when a

15   couple now goes to the IVF clinic even with the extra

16   embryos, they are saying yes in advance to the sad

17   necessity that some of these embryos are going to be

18   frozen in perpetuity or put to some kind of use.

19   They're simply compressing into one month or into one

20   visible     time   what   in   ordinary   biology    might   take

21   months.     Well, situations are fairly comparable.                I

22   think it is a matter, somewhat different when you

23   undertake to produce the embryos for the purpose of

24   exploiting them for use in which the destruction is --
                                                                             318

1    I won't say a minor thing, but it is the deliberate

2    exploitive disposition is what bothers me.

3                   Lastly,         to   Elizabeth,       if    I   might,    the

4    lurid cases are wonderful for focusing the mind and

5    the examples, both of the business about the child and

6    the exchange we had last time between Michael Sandel

7    and Robby George about dismembering one's 2-year-old

8    child for the organs and dismembering a blastocyst for

9    the cells spoke, it seems to me, volumes.                        It seems

10   like for my own sake a knockout case.

11                  On the other hand, I'll give you another

12   knockout case and we can wander away and ponder it.

13   Let's imagine that you've got the last couple on earth

14   and   a    couple    of    embryos      and    he     has      Alzheimer's

15   disease.      And the question is, do you sacrifice the

16   embryos for the sake of the cure of the living or do

17   you   allow    them       to    be    what    they        in   fact     are,

18   biologically        speaking,        the      seed        of    the     next

19   generation?      We can force ourselves not to look at

20   that because there are so many extra seeds, but if you

21   somehow focus the question and ask, then the merely

22   instrumental use of this seed, even though it doesn't

23   have a nervous system somehow begins to look rather

24   different.
                                                                    319

1                  There's a lot there to be quarreled with

2    and I probably abuse the privilege of the chair, but

3    there were a number of things floating around here

4    that only make the subject for me more complicated.

5                  What we'll sort out finally is we have to

6    move forward on this.            I think if I understand the

7    discussion here and Paul, you and I will have to work

8    out a way to find room for your so far eccentric, that

9    doesn't    mean     wrong,   but    unique   position    in    this

10   conversation, whether you want to have a separate --

11                 DR. McHUGH:        I'm glad you say it doesn't

12   mean wrong.    One could be --

13                 DR. KASS:         On this point we agreed last

14   time that we don't want to simply decide on the basis

15   of the wisdom of the vote of the majority to silence

16   any arguments sincerely held and properly defended.

17   It might very well be that an argument made and held

18   by   one   person    is   the    best   argument   and   we   would

19   deprive our readers of the benefit of having to weigh

20   that.

21                 I'm serious about that.

22                 DR. McHUGH:        I appreciate that.

23                 DR. KASS:         And it goes across the board.

24   I think we have to tidy up our work on the ethics of
                                                                          320

1    this and move on to the policy questions by the next

2    time we gather.

3                   I would like to ask everybody here, if

4    they     haven't already, if things that haven't been

5    passed before you don't already speak for you and

6    there    are   some    people      who    we    haven't   properly,        I

7    think, taken care of.           If you would write from 3 to 5

8    pages    and   if     it   turns    out    that    the    argument     is

9    shorter, less, a statement of your view not on the

10   question of ban or no ban, the policy question, but on

11   the question of the morality of cloning for biomedical

12   research and let's have it in two weeks and then we

13   can put this particular part of our discussion in a

14   form that can be circulated for everyone's approval.

15   I hope that's not too onerous.                   If there's anybody

16   who's writing another paper for another course, I'll

17   give you an extension, but tomorrow morning we meet at

18   8:30 to take up the enhancement discussion and then

19   the     regulatory     discussion.             Thank   you   for   your

20   endurance, your patience, your good will and we're

21   adjourned.

22                  (Whereupon, at 5:33 p.m., the meeting was

23   adjourned.)

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